Progranulin Oncogenic Network in Solid Tumors

Abstract

Progranulin is a pleiotropic growth factor with important physiological roles in embryogenesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor immune surveillance. However, the molecular mechanisms of progranulin oncogenic function are not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex and context-dependent role of progranulin in cancer. Here, we will review what is currently known about the function of progranulin in tumors, with a focus on its molecular mechanisms of action and regulation.

Full text

Citation: Ventura, E.; Ducci, G.;
Benot Dominguez, R.; Ruggiero, V.;
Belfiore, A.; Sacco, E.; Vanoni, M.;
Iozzo, R.V.; Giordano, A.; Morrione,
A. Progranulin Oncogenic Network
in Solid Tumors. Cancers 2023,15,
1706. https://doi.org/10.3390/
cancers15061706
Academic Editor: Alfonso Baldi
Received: 8 February 2023
Revised: 6 March 2023
Accepted: 8 March 2023
Published: 10 March 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
cancers
Review
Progranulin Oncogenic Network in Solid Tumors
Elisa Ventura 1,* , Giacomo Ducci 1,2,3 , Reyes Benot Dominguez 1, Valentina Ruggiero 1,4 ,
Antonino Belfiore 5, Elena Sacco 2,3 , Marco Vanoni 2,3 , Renato V. Iozzo 6, Antonio Giordano 1,7
and Andrea Morrione 1, *
1Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology,
Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
2Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
3SYSBIO (Centre of Systems Biology), ISBE (Infrastructure Systems Biology Europe), 20126 Milan, Italy
4Department of Pharmacological Sciences, Master Program in Pharmaceutical Biotechnologies,
University of Padua, 35131 Padua, Italy
5Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Catania,
Garibaldi-Nesima Hospital, 95122 Catania, Italy
6Department of Pathology, Anatomy and Cell Biology, Translational Cellular Oncology Program,
Sidney Kimmel Cancer Center, Sidney Kimmel Medical College at Thomas Jefferson University,
Philadelphia, PA 19107, USA
7Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
*Correspondence: elisa.ventura@temple.edu (E.V.); andrea.morrione@temple.edu (A.M.);
Tel.: +1-215-204-2450 (A.M.)
Simple Summary:
The growth factor progranulin plays an important pro-tumorigenic role in several
solid tumors and a growing number of studies suggest diagnostic and prognostic values for progran-
ulin in many tumor types. Progranulin exerts its pro-tumorigenic action by affecting both tumor cells
and the tumor microenvironment. However, the details of progranulin pro-oncogenic function are not
fully elucidated and recent evidence suggests a strong context-dependency of progranulin signaling.
In this review, we will summarize the current evidence supporting the progranulin pro-oncogenic
role, with a particular focus on what is currently known about progranulin molecular mechanisms of
action in cancer.
Abstract:
Progranulin is a pleiotropic growth factor with important physiological roles in embryo-
genesis and maintenance of adult tissue homeostasis. While-progranulin deficiency is associated
with a broad range of pathological conditions affecting the brain, such as frontotemporal dementia
and neuronal ceroid lipofuscinosis, progranulin upregulation characterizes many tumors, including
brain tumors, multiple myeloma, leiomyosarcoma, mesothelioma and epithelial cancers such as
ovarian, liver, breast, bladder, adrenal, prostate and kidney carcinomas. The increase of progranulin
levels in tumors might have diagnostic and prognostic significance. In cancer, progranulin has a
pro-tumorigenic role by promoting cancer cell proliferation, migration, invasiveness, anchorage-
independent growth and resistance to chemotherapy. In addition, progranulin regulates the tumor
microenvironment, affects the function of cancer-associated fibroblasts, and modulates tumor im-
mune surveillance. However, the molecular mechanisms of progranulin oncogenic function are
not fully elucidated. In bladder cancer, progranulin action relies on the activation of its functional
signaling receptor EphA2. Notably, more recent data suggest that progranulin can also modulate
a functional crosstalk between multiple receptor-tyrosine kinases, demonstrating a more complex
and context-dependent role of progranulin in cancer. Here, we will review what is currently known
about the function of progranulin in tumors, with a focus on its molecular mechanisms of action
and regulation.
Keywords: progranulin; solid tumors; RTKs
Cancers 2023,15, 1706. https://doi.org/10.3390/cancers15061706 https://www.mdpi.com/journal/cancers

Cancers 2023,15, 1706 2 of 21
1. Introduction
Progranulin is a pluripotent growth factor with important roles in several physio-
logical processes. Progranulin is expressed in both the embryo and placenta, where it
modulates embryo growth [
1
] and implantation [
2
], as well as placenta formation [
3
]. In
adult tissues, progranulin regulates tissue regeneration [
4
,
5
], promotes angiogenesis [
6
],
modulates the immune response [
7
,
8
] and is implicated in host defense against bacterial
infections [
8
,
9
]. In addition, progranulin is a key neurotrophic factor as, in fact, it pro-
motes neuronal survival and neurite growth [
10
,
11
], modulates neuroinflammation [
12
]
and regulates lysosome function in neurons [
13
,
14
]. On the other hand, progranulin dys-
regulation is involved in several diseases [
15
] and therefore has attracted attention as a
potential therapeutic target [
16
]. Progranulin mutations and heterozygous or homozygous
loss are associated with various and severe pathologies affecting the brain, including fron-
totemporal dementia and lysosomal storage diseases [
17
–
19
]. Dysregulated progranulin
is also implicated in autoimmune diseases [
20
]. Progranulin is overexpressed in several
cancer types, including hematological malignancies, where it exerts a critical role in tumor
progression. In this review, we focus on the role of progranulin in solid tumors, with a
particular attention to the known receptors and signaling pathways that are implicated in
progranulin pro-oncogenic action.
2. Progranulin Structure and Nomenclature
The growth factor progranulin is a modular protein containing seven and half non-
identical, cysteine-rich tandem repeats, known as granulin domains. Granulins A-G are full
modules, while p or paragranulin is the N-terminal half-module (Figure 1). The granulin
domain is evolutionary highly conserved [
21
] and has a unique structure consisting of
four
β
-hairpins held together by six disulfide bridges [
22
,
23
]. Progranulin homologs can
be found in a broad range of living organisms, ranging from plants to mammals [
21
]. In
invertebrates and fish, progranulin is coded by multiple GRN genes, whereas in the majority
of tetrapodes and in all mammals, progranulin is coded by a single gene. In humans, the
GRN gene is located on chromosome 17 (17q12.31) and contains a 5
0
non-coding exon and
12 coding exons. Each granulin repeat is coded by two adjacent exons [21].
Progranulin is secreted by regulated exocytosis (Figure 1) as a highly glycosylated
protein of around 70–80 kDa [
24
], as soluble protein or in exosomes [
25
]. Progranulin
N-glycosylation can occur on five different N-glycosylation sites with a prevalent addition
of fucosylated oligosaccharides [
26
]. Secreted progranulin can be processed into single
granulin modules of around 6 kDa (Figure 1), known as granulins, by various extracellular
proteases, including matrix metalloproteases (MMP) MMP-9, MMP-12 and MMP-14 [
27
],
elastase [
28
,
29
], proteinase 3 [
29
] and ADAM metallopeptidase with thrombospondin type
1 motif 7 (ADAMTS7) and 12 (ADAMTS12) [
30
]. On the other hand, progranulin binding
to the high-density lipoprotein (HDL)/apolipoprotein A-I complex [
31
] or the secretory
leukocyte protease inhibitor (SLPI) [
28
] protects progranulin from proteolytic cleavage,
thereby preserving progranulin precursor activity [28].
Granulins are biologically active but often exert opposing functions when compared
to the full-length progranulin precursor [
22
,
32
], and the levels of extracellular proteases
and protease inhibitors determine the relative abundance of progranulin and granulins
in the extracellular environment. In addition, there are progranulin fragments with an
intermediate size between progranulin and granulins, which are active as well, such as the
epithelial transforming growth factor (TGFe) [33].
Extracellular progranulin is internalized by endocytosis and sorted into lysosomes
(Figure 1). Interestingly, progranulin can also reach the lysosomes diverting from the
secretory pathway [13,34] (Figure 1). In lysosomes, progranulin is processed by cathepsin
L into granulins, which are quite stable in this subcellular compartment [
35
,
36
]. However,
the potential lysosomal function of granulins is still elusive [35,36].

Cancers 2023,15, 1706 3 of 21
Cancers 2023, 15, x FOR PEER REVIEW 3 of 22
Figure 1. Progranulin structure, processing and trafficking. The growth factor progranulin is a
modular protein containing seven and half non-identical, cysteine-rich tandem repeats, known as
granulin domains. Progranulin can be processed by several proteases into single granulin modules.
Progranulin is released into the extracellular environment by regulated exocytosis. Extracellular
progranulin can be internalized in a sortilin- or prosaposin-dependent manner and sorted into
lysosomes but can also reach the lysosomes diverting from the secretory pathway. In lysosomes,
progranulin is processed by cathepsin L into granulins. Whether progranulin might be endocytosed
in a sortilin- and prosaposin-independent manner through the binding to other receptors is still not
fully defined. ER: endoplasmic reticulum. TGN: trans-Golgi network.
Granulins are biologically active but often exert opposing functions when compared
to the full-length progranulin precursor [22,32], and the levels of extracellular proteases
and protease inhibitors determine the relative abundance of progranulin and granulins in
the extracellular environment. In addition, there are progranulin fragments with an
intermediate size between progranulin and granulins, which are active as well, such as
the epithelial transforming growth factor (TGFe) [33].
Extracellular progranulin is internalized by endocytosis and sorted into lysosomes
(Figure 1). Interestingly, progranulin can also reach the lysosomes diverting from the
secretory pathway [13,34] (Figure 1). In lysosomes, progranulin is processed by cathepsin
L into granulins, which are quite stable in this subcellular compartment [35,36]. However,
the potential lysosomal function of granulins is still elusive [35,36].
Since granulins and progranulins were initially discovered by different groups in
different contexts, the original nomenclature was quite confusing. Granulins were
originally identified as components of rat granulocytes granules and therefore called
granulins [37]. Simultaneously, they were identified in rat kidneys and called epithelins
[38]. Genetic studies later revealed that granulins and epithelins were coded by a single
gene and named either progranulin, proepithelin or granulin-epithelin precursor (GEP)
[39,40]. Guinea pig progranulin was first isolated from the acrosome and called acrogranin
[41]. Progranulin was also identified as a secreted growth factor from murine adipocytic
teratoma PC cells and named PC-cell-derived growth factor (PCDGF) [42–46], also known
as glycoprotein 88 kDa (GP88). Further studies demonstrated that all these proteins were
coded by the same gene [42,47].
Figure 1.
Progranulin structure, processing and trafficking. The growth factor progranulin is a
modular protein containing seven and half non-identical, cysteine-rich tandem repeats, known as
granulin domains. Progranulin can be processed by several proteases into single granulin modules.
Progranulin is released into the extracellular environment by regulated exocytosis. Extracellular
progranulin can be internalized in a sortilin- or prosaposin-dependent manner and sorted into
lysosomes but can also reach the lysosomes diverting from the secretory pathway. In lysosomes,
progranulin is processed by cathepsin L into granulins. Whether progranulin might be endocytosed
in a sortilin- and prosaposin-independent manner through the binding to other receptors is still not
fully defined. ER: endoplasmic reticulum. TGN: trans-Golgi network.
Since granulins and progranulins were initially discovered by different groups in
different contexts, the original nomenclature was quite confusing. Granulins were originally
identified as components of rat granulocytes granules and therefore called granulins [
37
].
Simultaneously, they were identified in rat kidneys and called epithelins [
38
]. Genetic
studies later revealed that granulins and epithelins were coded by a single gene and named
either progranulin, proepithelin or granulin-epithelin precursor (GEP) [
39
,
40
]. Guinea pig
progranulin was first isolated from the acrosome and called acrogranin [
41
]. Progranulin
was also identified as a secreted growth factor from murine adipocytic teratoma PC cells
and named PC-cell-derived growth factor (PCDGF) [
42
–
46
], also known as glycoprotein
88 kDa (GP88). Further studies demonstrated that all these proteins were coded by the
same gene [42,47].
3. Progranulin Binding Proteins
Progranulin pleiotropic action depends on its modular structure and its ability to
interact with a broad range of molecules, including extracellular soluble proteins, com-
ponents of the extracellular matrix, membrane proteins and proteins of the endoplasmic
reticulum (ER)/Golgi/lysosome network. The list of proteins interacting with progranulin
is continuously growing. Recently, new progranulin-binding proteins have been identified
using the ligand receptor capture technique in the neuron-like cell line NCS-34, but the
biological relevance of these novel interactions is still unknown [
48
]. Progranulin-binding
proteins can be divided into three main categories: (1) extracellular proteins; (2) mem-
brane proteins; and (3) ER/Golgi/lysosome network proteins. In addition, it has been

Cancers 2023,15, 1706 4 of 21
reported that progranulin and some granulin repeats can localize to the nucleus, where
they interact with the Tat/positive transcription elongation factor b (P-TEFb) and inhibit
Tat transactivation [49,50].
3.1. Progranulin Interaction with Extracellular Proteins
Secreted progranulin not only interacts with various extracellular proteases, which are
responsible for progranulin processing into granulins, as well as with proteins protecting
progranulin from proteolytic degradation, but also with different components of the ex-
tracellular matrix (ECM), including perlecan [
51
,
52
], cartilage oligomeric matrix protein
(COMP) [
53
] and extracellular matrix protein 1 [
54
]. The interaction of progranulin with
perlecan is mediated by granulin modules F and B and the first two-laminin- and epidermal
growth factor-like repeats of progranulin and perlecan, respectively [
51
], and modulates
tumor angiogenesis [
51
]. Progranulin interaction with COMP, mediated by the granulin
module A, potentiates progranulin-dependent stimulation of chondrocyte proliferation [
53
],
while the association of progranulin with extracellular matrix protein 1 negatively regulates
chondrogenesis and endochondral ossification [54].
3.2. Progranulin Interaction with Membrane Proteins and Membrane Receptors
Progranulin can bind several membrane proteins and cell membrane receptors, such
as sortilin [
13
], prosaposin [
55
], tumor-necrosis factor receptor (TNFR) 1 and 2 [
7
], DR3 [
56
],
four Notch receptors [
57
], DLK1 [
58
], EphA2 [
59
], RET [
48
] and Toll-like receptor (TLR)9 [
9
],
and these interactions are highly context-dependent.
Sortilin and prosaposin are principally responsible for progranulin lysosomal traffick-
ing. Sortilin belongs to the vacuolar protein sorting 10 (Vps10) family of receptors and its
binding to progranulin leads to progranulin endocytosis and trafficking into lysosomes [
13
]
(Figure 1). Secreted progranulin can interact with soluble prosaposin, in turn mediat-
ing progranulin internalization and lysosomal sorting by interacting with the mannose-
6-phosphate receptor (MRP6) or the low-density lipoprotein receptor-related protein 1
(LRP1) [
55
] (Figure 1). Both sortilin and prosaposin can mediate progranulin delivery
into lysosomes from either the extracellular space or the secretory pathway [
13
,
34
]. Evi-
dence suggests that the interactions of progranulin with sortilin and/or prosaposin are
particularly relevant in neurological cells [
60
]. Whether the interaction of progranulin with
other membrane receptors, including RTKs, leads to progranulin internalization is not well
established (Figure 1).
Progranulin binds to TNFR1 and TNFR2 on immune cells, mostly macrophages and
Tregs, competing with TNF-alpha for receptor binding, thereby inhibiting TNF-alpha pro-
inflammatory activity [
7
]. It is important to mention to that progranulin interaction with
TNFRs remains controversial, since other groups failed to confirm a direct binding of
progranulin to TNFRs [
61
–
63
]. These discrepancies might be due to technical differences in
the surface plasmon resonance (SPR) experimental approaches used by different groups [
64
].
In addition, progranulin binds to the TNFR1 homolog death receptor 3 (DR3), thereby
inhibiting DR3 binding to its natural ligand TNF-like ligand 1 (TL1A) [56].
Progranulin binds to Notch receptors by interacting with the extracellular domain of
the receptor, as demonstrated for the interaction with Notch1 [
57
]. Progranulin activates
Notch signaling pathways, promoting peripheral nerve regeneration and motor function
recovery [
57
]. In addition, progranulin interacts with DLK1, a modulator of the Notch
signaling pathway, but the biological relevance of this interaction is unknown [58].
In bladder cancer cells, progranulin binds to and activates ephrinA1-independent
EphA2 non-canonical signaling [
59
] favoring tumor progression, while in the neuron-like
cell line NSC-34, progranulin binds to RET and promotes its tyrosine-phosphorylation [
48
].
Finally, progranulin binds to both TLR9 and CpG oligonucleotides (CpG-ODNs) in
immune cells and endosomes, favoring TLR9 and CpG-ODNs interaction and potentiating
the innate immune response to bacterial infections [
9
]. Notably, it has been reported
that progranulin can activate other receptor-tyrosine kinases, including members of the

Cancers 2023,15, 1706 5 of 21
Eph family, such as EphA4 and EphB2 [
48
,
59
], EGFR [
48
,
59
,
65
], ErbB2 [
48
] and RYK [
65
].
However, it is not known whether progranulin activates these receptors by direct binding
or indirectly by activating functional cross-talks.
The domains responsible for progranulin interaction with some of its membrane bind-
ing partners have been characterized [
16
] and referenced herein. Progranulin interaction
with TNFR1, TNFR2 and DR3 is mediated by the granulin modules A, C and F and the
linkers P3, P4 and P5, while domains A, C, D and E allow the interaction with TLR9 and
CpG-ODNs [
16
]. Progranulin binds to sortilin through the last three amino acids in its
C-terminal (QLL) [
66
]. Multiple granulin domains, mostly granulins D and E, bind to the
linker region connecting saposins B and C in the prosaposin molecule [
67
]. On the receptors
side, the domains involved in progranulin binding are known only for TNF receptors
and DR3 [
68
]. Indeed, it has been demonstrated that progranulin binds the cysteine-rich
domains (CRD)2 and 3 of TNF receptors [
68
]. Considering that both CRD and EGF-like
domains can bind to progranulin and that at least one of these domains is part of the
extracellular region of all known progranulin-binding receptors, it is possible that CRD and
EGF-like domains are more likely involved in progranulin interactions with other receptors
than TNFR.
3.3. Progranulin Binding Partners Belonging to the ER/Golgi/Lysosome Network
Intracellular progranulin mostly localizes in the endoplasmic reticulum and lyso-
somes [
69
]. In the ER, progranulin binding partners include several chaperones, such as
endoplasmic reticulum protein (ERp)5, ERp57 and ERp72, heat-shock protein 70 (HSP70),
GRP94, binding immunoglobulin protein (BiP), calreticulin and protein disulfide isomerase
(PDI) [
69
] and references therein. It is believed that these chaperones assist in progranulin
folding and secretion [
69
]. In lysosomes, progranulin acts as a co-chaperone by interacting
with various hydrolases, such as glucocerebrosidase (GCase), cathepsin D (CSTD) and
β
-hexosaminidase (HexA) [
69
]. The relevance of progranulin function as a lysosomal
protein is exemplified by the phenotypes associated with progranulin loss, as reviewed by
Chitramuthu et al. [
17
]. Indeed, progranulin deficiency is usually associated with lysosomal
disfunctions with progranulin homozygous loss causing cerebroid lipofuscinosis, a severe
lysosomal disorder [
17
]. On the contrary, GRN haploinsufficiency leads to frontotemporal
dementia (FTD), a disorder characterized by the neurodegeneration of the frontal and tem-
poral lobes, and lysosome disfunction associated with the presence of neuronal inclusions
containing fragments of ubiquitinated TDP-43 [17].
4. Progranulin in Solid Tumors
Progranulin was originally identified as a soluble factor promoting cancer progression
and regulating wound healing [
4
,
70
–
72
]. Later studies demonstrated that progranulin is
upregulated in many solid tumors, where it promotes tumor cell proliferation, migration,
invasion, adhesion,
in vivo
tumor formation and maintenance of cancer stem cells (CSC)
(Table 1). In addition, progranulin contributes to the establishment and maintenance of a
tumor microenvironment (TME) that favors tumor progression by modulating the function
of several cellular components of the TME, including endothelial cells, immune cells and
cancer-associated fibroblast (CAF) (Table 1) [73].

Cancers 2023,15, 1706 6 of 21
Table 1. Progranulin action in cancer. For references, see [15,74] and references throughout the text.
Progranulin Autocrine Function on Tumor Cells
Cell proliferation Colorectal cancer, lung carcinoma, cervical cancer, prostate carcinoma, adrenal carcinoma,
laryngeal carcinoma, breast carcinoma.
Cell migration and invasion Breast cancer, colorectal cancer, bladder cancer, prostate carcinoma, adrenal carcinoma,
hepatocellular carcinoma, ovarian carcinoma, mesothelioma.
CSC maintenance Hepatocellular carcinoma, breast carcinoma, glioblastoma.
Progranulin Modulation of the Tumor Microenvironment
Tumor angiogenesis and
lymphangiogenesis Colorectal cancer, breast cancer, mesothelioma, esophageal squamous cell carcinoma.
Tumor immune evasion Hepatocellular carcinoma, metastatic pancreatic cancer, pancreatic ductal carcinoma,
breast carcinoma.
Stimulation of fibroblasts and
myofibroblasts function Breast carcinoma, pancreatic ductal adenocarcinoma, colorectal carcinoma.
Progranulin Axis as a Biomarker in Cancer
Diagnostic and/or prognostic
and/or predictive marker
Breast carcinoma, prostate carcinoma, ovarian epithelial cancers, colorectal carcinoma,
bladder cancer, non-small cell lung carcinoma, astrocytoma, glioblastoma, oral squamous
cell carcinomas, biliary tract carcinoma, gastrointestinal tumors, papillary thyroid cancer.
Progranulin and Resistance to Anticancer Therapies
Chemotherapy Breast carcinoma, ovarian, colorectal, and hepatocellular carcinomas, glioblastoma,
bladder cancer.
Radiation therapy Prostate cancer.
Progranulin as a Therapeutic Target in Cancer
Progranulin inhibition via genetic
depletion or neutralizing antibodies
Breast carcinoma, ovarian cancer, hepatocellular carcinoma, bladder cancer.
4.1. Progranulin Autocrine Function on Tumor Cells
4.1.1. Progranulin and Tumor Cell Proliferation, Migration and Invasion
The role of progranulin in promoting tumor cell proliferation and motility has been
well established. Progranulin promotes cell proliferation in many tumor models, as exten-
sively reviewed by Bateman et al. and Arechavelata-Velasco et al. [
15
,
74
], but the molecular
mechanisms are not completely understood. Some evidence suggests that progranulin can
modulate CDK4 activity, cyclin D1 and cyclin B levels, as well as c-myc function by activat-
ing the AKT and MAPK signaling pathways [
74
–
76
]. In addition, recently published data
support the evidence of crosstalk between progranulin and the TGF-
β
signaling pathway,
which affects cell proliferation [77].
A critical role for progranulin in mediating cell motility has been demonstrated in
many tumor models with multiple mechanisms proposed. Indeed, progranulin promotes
an epithelial-to-mesenchymal transition (EMT) process, thereby favoring the acquisition of
a highly migratory and invasive phenotype [15,74].
In bladder cancer, progranulin promotes cell migration and invasion by inducing the
formation of a molecular complex containing focal adhesion kinase (FAK) and paxillin,
in an ERK1/2-dependent manner [
78
] (Figure 2). In addition, in bladder cancer, progran-
ulin interacts with the F-actin-binding protein drebrin [
79
]. In this tumor model, drebrin
mediates progranulin-dependent cell migration and invasion by modulating F-actin remod-
eling [
79
]. Recently, we have demonstrated that in mesothelioma, progranulin regulates
FAK phosphorylation, thereby modulating focal adhesion (FA) turnover, particularly FA
disassembly, which is a critical step in cell motility [65].

Cancers 2023,15, 1706 7 of 21
Cancers 2023, 15, x FOR PEER REVIEW 7 of 22
Figure 2. Progranulin signaling in cancer. Progranulin oncogenic signaling is highly dependent on
progranulin-dependent activation of AKT and/or MAPK signaling pathways. In colorectal cancer,
progranulin promotes AKT activation in a TNFR2-dependent manner. In prostate cancer, sortilin
acts as a negative regulator of progranulin by promoting progranulin internalization and
degradation, leading to the inhibition of the AKT pathway. In turn, progranulin mediates sortilin
ubiquitination and degradation to sustain its pro-oncogenic activity. In bladder cancer, progranulin
binds to and activates EphA2, leading to AKT and MAPK activation. In turn, AKT and MAPK
sustain EphA2 phosphorylation at Ser897. In mesothelioma, progranulin-dependent activation of
the AKT and MAPK signaling pathways relies on EGFR and RYK. Progranulin directly interacts
with TNFRs, sortilin and EphA2. Whether progranulin promotes EGFR and RYK phosphorylation
and activation directly by physically interacting with the receptors, or in an indirect manner, or
whether progranulin promotes the formation of a complex including EGFR, RYK and EphA2
requires further investigation.
4.1.2. Progranulin and the Maintenance of CSC
Progranulin has been implicated in the maintenance of CSC, a subpopulation of
tumor cells with stemness-like properties and tumor-initiating ability, often determining
tumor recurrence [80,81]. Cheung et al. described progranulin as an oncofetal protein
detected in fetal liver and hepatic cancer cell subpopulations expressing stemness
markers, such as Nanog, Oct4 and Sox2, and showing an increased capacity to form
tumors in vivo and induce resistance to chemotherapy [82]. In glioblastoma, progranulin
sustained the expression of stemness genes, including CD133, CD44 and ABG2 [83]. In
addition, progranulin depletion reduced self-renewal and multilineage differentiation
capacity of R1S1 glioblastoma cells, contributing to temozolomide resistance [83]. In breast
cancer, progranulin promoted proliferation of CSC and caused their dedifferentiation in
a sortilin-dependent manner, suggesting a critical role for progranulin and sortilin in the
maintenance of breast CSC [84,85].
4.2. Progranulin and the Tumor Microenvironment
4.2.1. Progranulin in Tumor Angiogenesis and Lymphangiogenesis
Progranulin has an important role in physiological angiogenesis. Progranulin is
expressed at low levels in quiescent endothelial cells, but progranulin expression is
upregulated following endothelial cell activation during wound healing, tissue repair and
Figure 2.
Progranulin signaling in cancer. Progranulin oncogenic signaling is highly dependent on
progranulin-dependent activation of AKT and/or MAPK signaling pathways. In colorectal cancer,
progranulin promotes AKT activation in a TNFR2-dependent manner. In prostate cancer, sortilin acts
as a negative regulator of progranulin by promoting progranulin internalization and degradation,
leading to the inhibition of the AKT pathway. In turn, progranulin mediates sortilin ubiquitination
and degradation to sustain its pro-oncogenic activity. In bladder cancer, progranulin binds to and
activates EphA2, leading to AKT and MAPK activation. In turn, AKT and MAPK sustain EphA2
phosphorylation at Ser897. In mesothelioma, progranulin-dependent activation of the AKT and
MAPK signaling pathways relies on EGFR and RYK. Progranulin directly interacts with TNFRs,
sortilin and EphA2. Whether progranulin promotes EGFR and RYK phosphorylation and activation
directly by physically interacting with the receptors, or in an indirect manner, or whether progranulin
promotes the formation of a complex including EGFR, RYK and EphA2 requires further investigation.
4.1.2. Progranulin and the Maintenance of CSC
Progranulin has been implicated in the maintenance of CSC, a subpopulation of tumor
cells with stemness-like properties and tumor-initiating ability, often determining tumor
recurrence [
80
,
81
]. Cheung et al. described progranulin as an oncofetal protein detected
in fetal liver and hepatic cancer cell subpopulations expressing stemness markers, such
as Nanog, Oct4 and Sox2, and showing an increased capacity to form tumors
in vivo
and
induce resistance to chemotherapy [
82
]. In glioblastoma, progranulin sustained the expres-
sion of stemness genes, including CD133,CD44 and ABG2 [
83
]. In addition, progranulin
depletion reduced self-renewal and multilineage differentiation capacity of R1S1 glioblas-
toma cells, contributing to temozolomide resistance [
83
]. In breast cancer, progranulin
promoted proliferation of CSC and caused their dedifferentiation in a sortilin-dependent
manner, suggesting a critical role for progranulin and sortilin in the maintenance of breast
CSC [84,85].
4.2. Progranulin and the Tumor Microenvironment
4.2.1. Progranulin in Tumor Angiogenesis and Lymphangiogenesis
Progranulin has an important role in physiological angiogenesis. Progranulin is
expressed at low levels in quiescent endothelial cells, but progranulin expression is up-
regulated following endothelial cell activation during wound healing, tissue repair and

Cancers 2023,15, 1706 8 of 21
physiological angiogenesis in the developing placenta [
3
,
4
]. Progranulin action in angiogen-
esis has been also demonstrated using transgenic mice. Indeed, progranulin overexpression
in endothelial cells caused high rates of perinatal mortality because of expanded vessels size
and progressive disruption of vascular integrity [
6
]. In many tumor models, progranulin
has been detected in tumor-associated vasculature [
51
,
86
–
88
]. In colorectal cancer, progran-
ulin promotes VEGF expression in a TNFR2/AKT/MAPK-dependent manner [
89
] and a
similar action has been suggested in breast cancer cells, as well [
90
]. In agreement with the
role of progranulin in promoting VEGF expression, progranulin levels positively correlate
with VEGF expression and microvessel density in several tumor models, including breast
carcinoma [
90
,
91
], esophageal squamous cell carcinoma [
87
] and colorectal cancer [
89
].
Notably, it has been suggested that progranulin might also promote angiogenesis in a
VEGF-independent manner in mesothelioma [
92
]. In addition, progranulin interacts with
the growth factor midkine (MK), a heparin-binding growth factor, and, in association with it,
promotes HUVEC cells proliferation, migration and tubulogenesis [
93
]. Interestingly, it has
been suggested that, in esophageal cancer, progranulin can also sustain lymphangiogenesis
by favoring the expression of VEGF-C [94].
4.2.2. Progranulin and Tumor Immune Evasion
Tumors develop multiple mechanisms to escape the host’s immune surveillance [
95
].
Growing evidence suggests that progranulin contributes to tumor immune evasion, not
only by inhibiting immune cells but also by rendering tumor cells less immunogenic.
Indeed, progranulin inhibits T lymphocytes proliferation and induces the generation of
regulatory T lymphocytes (Treg) [96].
In hepatocellular carcinoma, progranulin rendered tumor cells resistant to natural
killer (NK) cytotoxicity by promoting the downregulation of MHC class I chain-related
molecule A (MICA) and upregulation of human leukocyte antigen E (HLA-E), the ligands
of NK activator receptor NK group 2 member D (NKG2D) and NK inhibitory receptor
CD94/NKG2A, respectively [
97
]. In agreement, progranulin inhibition restored NK cell
activity [98].
In metastatic pancreatic cancer, macrophage-derived progranulin promoted CD8+
exclusion, contributing to tumor resistance to immune checkpoint inhibitors [
99
]. In the
murine melanoma tumor model B16, progranulin promoted tumor growth by reducing
recruitment of NK cells to the tumor microenvironment [100].
Notably, in breast cancer, progranulin promoted the expression of PD-L1 on tumor-
associated macrophages (TAM) and favored their M2 polarization, leading to lymphocytes
CD8+ exclusion [
101
]. In another study, exosomes derived from GRN
−/−
TAM inhibited
breast cancer cell migration and invasion [
102
]. Finally, in pancreatic ductal carcinoma,
high progranulin levels are associated with reduced MCHI expression and a lack of CD8+T
lymphocyte infiltration [103].
4.2.3. Progranulin and Stromal Fibroblasts/Myofibroblast
The first evidence supporting progranulin action in modulating tumor stromal fibrob-
last function was reported by Elkabets et al. in 2011 [
104
]. The authors observed that
MDA-MB-231 breast cancer cells subcutaneously implanted on one flank in mice promoted
the expression of progranulin in Sca
−
/cKit
−
/CD45+ bone marrow-derived cells. The
activated and progranulin-expressing Sca
−
/cKit
−
/CD45+ bone marrow-derived cells
were then recruited to the site of the indolent tumor HMLER-HR, which was injected
on the other flank, where they released progranulin, thereby stimulating expression and
production of chemokines, cytokines, growth factors and matrix remodeling proteases by
stromal fibroblasts and myofibroblasts, favoring growth and progression of these indolent
tumors [
104
]. In a murine model of pancreatic ductal adenocarcinoma, Nielsen et al. demon-
strated that metastasis-associated macrophages (MAMs) activated resident hepatic stellate
cells into myofibroblasts by secreting progranulin, in turn creating a fibrotic TME suitable
for metastatic tumor growth [
105
]. Interestingly, the authors also observed high expression

Cancers 2023,15, 1706 9 of 21
levels of progranulin in hepatic MAMs and circulating monocytes derived from pancreatic
ductal adenocarcinoma patients [
105
]. Finally, in colorectal cancer, tumor cell-derived
progranulin has a role in promoting the conversion of fibroblasts into CAFs [106].
4.3. Diagnostic, Prognostic and Predictive Roles of the Progranulin Axis in Cancer
Progranulin is upregulated in many tumors, as compared to normal tissues, suggesting
that progranulin can serve as a biomarker for several cancer types, including breast, prostate,
ovarian, colon and bladder cancers, non-small cell lung carcinoma and brain tumors.
In breast cancer, progranulin has been proposed as a diagnostic, predictive and prog-
nostic marker, as progranulin levels correlated with tumor angiogenesis, tumor size and
the presence of metastasis in lymph nodes [
107
–
113
]. In addition, in patients with estro-
gen receptor-positive invasive ductal carcinoma, high progranulin levels in breast tumor
tissue sections inversely correlated with disease-free tissue and overall survival rates and
were predictive of recurrence risk and increased mortality [
109
]. Progranulin serum levels
were higher in breast cancer patients when compared to healthy individuals and were
predictive of recurrence in hormone-receptor-positive breast cancer patients treated with
tamoxifen [
114
]. In metastatic breast cancer patients, progranulin serum levels were associ-
ated with disease progression and response to therapy [
112
]. Notably, Berger et al. reported
that the co-expression of progranulin and sortilin identified a highly malignant subgroup
of breast cancers [115].
Progranulin expression is higher in prostate tumors than in normal prostate tis-
sue [
116
,
117
]. In prostate cancer patients, progranulin serum levels change with age
and Gleason score, with lower progranulin serum levels being associated with better over-
all survival [
118
]. In addition, progranulin serum levels in combination with miR-486
levels might work as biomarkers predictive for therapy decisions in elderly prostate cancer
patients [
119
]. Furthermore, progranulin expression in prostate cancer tissues is an inde-
pendent prognostic factor for overall, disease-specific, and relapse-free survival in prostate
cancer patients [120].
Similarly, ovarian epithelial cancers (EOC) showed progranulin upregulation as com-
pared to normal ovarian tissues and a negative correlation between progranulin mRNA
levels and poor overall survival in ovarian tumors [
121
]. Progranulin expression was
demonstrated in both primary and metastatic EOC, as well as tumor stromal cells, and the
presence of progranulin-positive stromal cells in untreated primary tumors was associated
with reduced overall survival [
86
]. In addition, progranulin serum levels can have prognos-
tic value for ovarian cancer patients [
122
], particularly in patients with advanced stages of
EOC [123].
Colorectal cancer (CRC) tissues showed increased levels of progranulin as compared
to normal colorectal tissues, and progranulin levels positively correlated with Ki67 and
VEGF-A expression [
89
]. Furthermore, high progranulin levels were associated with poor
recurrence-free survival in a retrospective analysis of CRC patients who underwent curative
resection [124].
Progranulin is detectable in urine [
125
] and its levels are proposed as both diagnostic
and prognostic markers for bladder cancer [
126
,
127
]. Recent data have indicated that pro-
granulin levels in tumor cells and tumor-infiltrating immune cells likely work as prognostic
markers in muscle-invasive urothelial bladder cancer, where high progranulin levels in
tumor cells are considered a negative prognostic marker, while high progranulin levels in
tumor-infiltrating immune cells are associated with better prognosis [
128
]. Interestingly,
immunohistochemical analysis of progranulin and EphA2 expression showed progranulin
and EphA2 upregulation in urothelial carcinoma tissues [
125
,
129
]. In addition, the expres-
sion of drebrin, a mediator of progranulin action in bladder cancer, is significantly higher
in high grade versus low grade urothelial carcinoma tissues [79].
Progranulin expression is not detected in normal lung tissues or in small cell lung
carcinoma, but it is expressed in lung adenocarcinoma, squamous cell carcinoma and
non-small cell lung carcinoma (NSCLC) [
110
,
130
]. In NSCLC patients, progranulin tissue

Cancers 2023,15, 1706 10 of 21
and serum levels are prognostic factors for recurrence [
110
,
130
], and high progranulin
levels in bronchoalveolar lavage fluids of NSCLC patients were associated with shorter
overall survival [131].
Progranulin levels were upregulated in astrocytoma and positively correlated with
pathological grade [
88
]. In addition, a prognostic value was demonstrated for progranulin
levels in glioblastoma patients [
88
]. Interestingly, progranulin levels increase in cere-
brospinal fluids of patients presenting with lymphoma or carcinoma brain metastasis [
132
].
Finally, the potential use of progranulin as a prognostic marker is also currently under
investigation in other tumors, such as oral squamous cell carcinomas [
133
], advanced biliary
tract carcinoma [134], gastrointestinal tumors [135] and papillary thyroid cancer [136].
4.4. Progranulin Role in Tumor Resistance to Anticancer Therapies
Progranulin contributes to therapy resistance in many cancer types. However, the
precise molecular mechanisms by which progranulin exerts this action are not completely
understood.
The first report suggesting a role for progranulin in conferring resistance to chemother-
apy was in breast cancer, as Tangkeangsirisin et al. observed that progranulin counteracted
tamoxifen-induced apoptosis in breast cancer cells by inhibiting bcl-2 downregulation and
preventing poly (ADP-ribose) polymerase cleavage [
137
]. It was later reported that, in
Her-2 overexpressing breast cancer cells, progranulin conferred resistance to trastuzumab
by promoting ErbB2/Her-2 phosphorylation [
107
]. In another study, the authors demon-
strated that progranulin can also confer resistance to the aromatase inhibitor letrozole in
breast cancer cells [138].
Several reports indicate that progranulin promotes resistance to platinum-based
chemotherapy agents in various cancer types, including ovarian [
139
], colorectal [
140
],
hepatocellular [
141
] and bladder cancer [
142
]. In hepatocellular carcinoma, a role for
progranulin in promoting resistance to doxorubicin has also been demonstrated [
141
].
Progranulin-dependent expression of adenosine triphosphate–dependent binding cassette
(ABC)B5 drug transporter is likely the potential molecular mechanism by which progran-
ulin promotes tumor cell resistance to platinum-based and doxorubicin drugs [143].
In glioblastoma, progranulin promoted resistance to temozolomide by enhancing the
expression of DNA repair and stemness genes [83].
In addition to chemotherapy, progranulin also contributes to radiation-therapy re-
sistance, as reported in prostate cancer cells [
144
]. Finally, progranulin can contribute to
tumor immune escape, thereby conferring resistance to immune checkpoint inhibitors [
99
].
4.5. Progranulin as a Therapeutic Target in Cancer
Progranulin’s pro-tumorigenic role makes it an attractive target for cancer therapy [
16
,
60
].
Many studies have demonstrated the efficacy of progranulin-inhibition in reducing
in vitro
tumor cell proliferation, migration and invasion, as well as
in vivo
tumor formation in
multiple tumor models, as reviewed by Arechavaleta-Velasco et al. [
74
]. Current research
is mostly focusing on the development of monoclonal neutralizing antibodies specific
for progranulin. Notably, in February 2022, the first in-human phase 1 study of the anti-
progranulin antibody AG01 [
76
] was started in patients with advanced solid tumors,
particularly triple negative breast cancer, hormone-resistant breast cancer, NSCLC and
mesothelioma patients (ClinicalTrials.gov Identifier: NCT05627960).
5. Progranulin Signaling in Cancer
Progranulin oncogenic signaling is highly dependent on AKT and/or MAPK path-
ways, which are the signaling cascades typically activated by growth factor receptors.
Indeed, progranulin evokes the activation of AKT and MAPK signaling in many tu-
mor models, including colorectal [
89
], bladder [
59
,
78
,
79
,
129
,
142
,
145
], breast [
76
], ovar-
ian [
121
], prostate [
117
,
146
], cervical [
147
,
148
] and gastric cancers [
149
], hepatocellular
carcinoma [
150
,
151
], NSCLC [
152
], esophageal cell squamous carcinoma [
153
], cholangio-

Cancers 2023,15, 1706 11 of 21
carcinoma [
75
,
154
] and mesothelioma [
65
]. AKT and MAPK activation are key events in
progranulin oncogenic action, since these two signaling pathways are essential for cell
proliferation and survival, migration and invasion [155] (Figure 2).
Progranulin-mediated regulation of cell motility also relies on FAK activity (Figure 3).
Indeed, in adrenal carcinoma cells, progranulin promotes FAK tyrosine-phosphorylation [
4
].
Furthermore, in bladder cancer, progranulin-dependent activation of MAPK favors the
formation of a complex containing paxillin and FAK, thereby promoting cell migration and
invasion [
78
]. Recently, we have demonstrated that in mesothelioma cells, progranulin
modulates the phosphorylation of FAK at Y397, affecting focal adhesion kinetics and, more
specifically, the process of FA assembly/disassembly [
65
]. Progranulin-dependent regula-
tion of FA turnover is likely the mechanism by which progranulin influences mesothelioma
cell motility [
65
]. Since FAK is a key mediator of integrin signaling, these data might also
suggest a potential role for progranulin in modulating integrin function. There are some
indications that this might be the case, as in fact it has been demonstrated that progranulin
promoted prostate cancer cells’ adhesion to bone marrow endothelial cells (BMEC) in an
NF-kB and integrin-
α
4-dependent manner [
156
]. In addition, integrin-
α
3 was among the
potential progranulin membrane binding proteins recently identified in NSC-34 cells by
Chitramuthu et al. [48].
Cancers 2023, 15, x FOR PEER REVIEW 12 of 22
5. Progranulin Signaling in Cancer
Progranulin oncogenic signaling is highly dependent on AKT and/or MAPK
pathways, which are the signaling cascades typically activated by growth factor receptors.
Indeed, progranulin evokes the activation of AKT and MAPK signaling in many tumor
models, including colorectal [89], bladder [59,78,79,129,142,145], breast [76], ovarian [121],
prostate [117,146], cervical [147,148] and gastric cancers [149], hepatocellular carcinoma
[150,151], NSCLC [152], esophageal cell squamous carcinoma [153], cholangiocarcinoma
[75,154] and mesothelioma [65]. AKT and MAPK activation are key events in progranulin
oncogenic action, since these two signaling pathways are essential for cell proliferation
and survival, migration and invasion [155] (Figure 2).
Progranulin-mediated regulation of cell motility also relies on FAK activity (Figure
3). Indeed, in adrenal carcinoma cells, progranulin promotes FAK tyrosine-
phosphorylation [4]. Furthermore, in bladder cancer, progranulin-dependent activation
of MAPK favors the formation of a complex containing paxillin and FAK, thereby
promoting cell migration and invasion [78]. Recently, we have demonstrated that in
mesothelioma cells, progranulin modulates the phosphorylation of FAK at Y397, affecting
focal adhesion kinetics and, more specifically, the process of FA assembly/disassembly
[65]. Progranulin-dependent regulation of FA turnover is likely the mechanism by which
progranulin influences mesothelioma cell motility [65]. Since FAK is a key mediator of
integrin signaling, these data might also suggest a potential role for progranulin in
modulating integrin function. There are some indications that this might be the case, as in
fact it has been demonstrated that progranulin promoted prostate cancer cells’ adhesion
to bone marrow endothelial cells (BMEC) in an NF-kB and integrin-α4-dependent manner
[156]. In addition, integrin-α3 was among the potential progranulin membrane binding
proteins recently identified in NSC-34 cells by Chitramuthu et al. [48].
Figure 3. Progranulin modulates FAK activity. In bladder cancer, progranulin-dependent activation
of ERK1/2 promotes the formation of a complex containing FAK, paxillin and ERK1/2, thereby
promoting cell motility. In addition, in bladder cancer, progranulin interacts with the F-actin-
binding protein drebrin, promoting F-actin remodeling. However, the mechanism by which
progranulin interacts with drebrin is still unknown and could be dependent on receptor-mediated
progranulin internalization. In mesothelioma cells, progranulin modulates the phosphorylation of
FAK, affecting the dynamics of focal adhesion assembly/disassembly and F-actin remodeling. RYK
action in progranulin-dependent modulation of FAK in mesothelioma is still not well defined.
Figure 3.
Progranulin modulates FAK activity. In bladder cancer, progranulin-dependent activation
of ERK1/2 promotes the formation of a complex containing FAK, paxillin and ERK1/2, thereby
promoting cell motility. In addition, in bladder cancer, progranulin interacts with the F-actin-binding
protein drebrin, promoting F-actin remodeling. However, the mechanism by which progranulin
interacts with drebrin is still unknown and could be dependent on receptor-mediated progranulin
internalization. In mesothelioma cells, progranulin modulates the phosphorylation of FAK, affecting
the dynamics of focal adhesion assembly/disassembly and F-actin remodeling. RYK action in
progranulin-dependent modulation of FAK in mesothelioma is still not well defined.
In addition to AKT, ERK1/2 and FAK, progranulin can also sustain the activity of
signal transducer and transcription activator3 (STAT3) [
157
]. Indeed, in colorectal cancer
cells, progranulin physically interacted with STAT3, evoking its phosphorylation and
pro-oncogenic downstream signaling [157].
Although progranulin-dependent activation of AKT and MAPK and, to a lesser extent,
FAK and STAT3 has been extensively demonstrated, how progranulin leads to their activa-
tion is not fully defined and evidence suggests context-dependent mechanisms (Figure 2).

Cancers 2023,15, 1706 12 of 21
In colorectal cancer cells and in human vascular endothelial cells, TNFR2 is required for
progranulin-dependent stimulation of the AKT pathway [
89
] (Figure 2). On the other
hand, in breast cancer, progranulin action is mediated by sortilin, as, in fact, progranulin
promoted breast cancer CSC’ expansion in a sortilin-dependent manner [
84
]. In agree-
ment with a role for sortilin in supporting progranulin oncogenic action, sortilin inhibition
counteracted progranulin-dependent breast cancer progression and CSC expansion [
84
,
85
].
Furthermore, co-expression of progranulin and sortilin might work as a biomarker, which
identifies a highly malignant subgroup of breast cancers [
115
]. By contrast, in prostate can-
cer cells, sortilin acts as a negative modulator of progranulin activity, as its overexpression
reduced progranulin levels by promoting clathrin-dependent progranulin internalization
and degradation, leading to a reduction in AKT activation, cell proliferation, migration,
invasion and anchorage-independent growth [
146
,
158
,
159
] (Figure 2). Significantly, we
later demonstrated that progranulin downregulated sortilin protein levels independently
of transcription by mediating sortilin ubiquitination, internalization via clathrin-dependent
endocytosis and trafficking into early endosomes for lysosomal degradation. These results
suggest a fine-tuned regulatory feedback mechanism, whereby sortilin downregulation en-
sures sustained progranulin-mediated oncogenic action in prostate cancer [
159
]. However,
whether this regulatory mechanism is conserved in other tumor models requires further
investigation. Interestingly, in bladder cancer, the F-actin-binding protein drebrin interacts
with progranulin and is involved in mediating progranulin-dependent activation of the
AKT and MAPK pathways [79].
An important step forward in deciphering progranulin oncogenic mechanisms of
action was the identification of EphA2 as the functional progranulin receptor in bladder
cancer [
59
]. EphA2 is a member of the Eph family of RTKs and its role in cancer is controver-
sial. EphA2 activation by its canonical ligand, ephrin-A1, evokes EphA2 canonical signaling
inhibiting cancer cell migration and invasion [
160
]. Conversely, ephrin-A1-independent
and AKT- or RSK-dependent phosphorylation of EphA2 at Ser 897 determines EphA2 pro-
oncogenic activity [
161
,
162
]. In bladder cancer, progranulin binds to and triggers EphA2
tyrosine-phosphorylation, with consequent activation of the AKT and MAPK signaling
pathways, which in turn promote EphA2 phosphorylation at Ser 897 [
59
,
129
] (Figure 2).
In this tumor model, the progranulin/EphA2 axis drives tumor cell migration, invasion,
anchorage-independent growth, in vivo tumor formation and cisplatin-resistance [129].
Recently, we have demonstrated that in mesothelioma cells, EphA2 is not the major
progranulin signaling receptor and progranulin action is instead mediated by EGFR and
RYK, a co-receptor of the Wnt pathway [
65
] (Figure 2). Notably, in this tumor model, pro-
granulin sustains AKT and MAPK activation and the phosphorylation of EphA2 at Ser 897,
as in bladder cancer cells. However, the contribution of EphA2 activation is not clearly de-
fined in mesothelioma cells, where we identified by RTK arrays that progranulin promoted
tyrosine-phosphorylation of EGFR and RYK. Significantly, in this experimental approach,
we did not detect any Tyr-phosphorylation of EphA2 [
65
]. Progranulin-dependent EGFR
activation was not totally surprising, as it has been observed in other models, including
bladder cancer [
59
], breast cancer [
84
] and mammary epithelial cells [
48
]. However, we do
not know whether progranulin modulates EGFR activity directly, by physically interacting
with the receptor, or in an indirect manner. The modulation of RYK activity by progranulin
is of particular interest. RYK is a Wnt-binding RTK with a role as a co-receptor for both
canonical (
β
-catenin-dependent) and non-canonical (
β
-catenin-independent) Wnt signaling
pathways [
163
]. Interestingly, RYK does not likely have kinase activity, suggesting that RYK
action depends on functional interactions with other receptors. Indeed, it has been demon-
strated that RYK forms complexes with Frizzled (FDZ) receptors, but also with other RTKs,
such as Eph receptors [
163
]. There are data suggesting that some Eph receptors can mediate
RYK phosphorylation [
164
,
165
], but the functional relevance of RYK interaction with other
RTKs is still unknown. It is tempting to hypothesize that, in mesothelioma, EGFR could be
involved in progranulin-stimulated RYK tyrosine-phosphorylation and that progranulin
signaling might depend on EGFR and RYK physical and functional interactions. In addition,

Cancers 2023,15, 1706 13 of 21
because EGFR modulates EphA2 phosphorylation at Ser897 in mesothelioma cells [
65
],
we can also hypothesize that EGFR could promote RYK phosphorylation indirectly by
modulating EphA2 activity (Figure 2). The potential role played by RYK in cancer is, at the
moment, not well defined, but there are a few studies demonstrating increased RYK expres-
sion in some tumor models, such as glioblastoma [
166
], acute lymphoblastic leukemia and
acute myeloid leukemia [
167
] and others [
163
]. In addition, a role for RYK in mediating
cell migration and anchorage-independent growth in cancer cells has been suggested [
166
].
Thus, it would be interesting to investigate whether progranulin oncogenic action is medi-
ated, at least in part, by RYK and the Wnt pathway. Notably, previous reports suggested
that progranulin might modulate the Wnt pathway, as in fact there is a correlation between
progranulin haploinsufficiency and dysregulation of Wnt signaling [
168
–
172
]. Interestingly,
Rosen et al. demonstrated that FTD caused by GRN haploinsufficiency is partially mediated
by changes in Wnt signaling [
168
]. Notably, Wnt pathway dysregulation, characterized by
the upregulation of genes belonging to Wnt canonical signaling and downregulation of
negative regulators of Wnt signaling, is an early event in GRN haploinsufficient FTD and
precedes the onset of the neurodegenerative process [
168
,
172
]. However, how progranulin
regulates the Wnt pathway is not yet defined. Most of the studies establishing a connection
between GRN haploinsufficiency and Wnt dysregulation focused on neuronal cells derived
from animal models or patients affected by frontotemporal dementia [
168
–
170
], but there
are also studies investigating other pathological conditions associated with a reduction in
progranulin levels, such as intervertebral disc degeneration [
171
]. It would be interesting to
investigate whether RYK might have a role in this context, and whether progranulin might
either interfere or potentiate Wnt signaling pathways in cancer by functionally interacting
with RYK.
Finally, progranulin can also activate additional receptors, including other members
of the Eph family of RTKs [
48
,
59
], ErBB2 and RET [
48
]. Whether these receptors might
contribute to progranulin oncogenic action remains unexplored. Overall, these data sug-
gest a complex modulation of progranulin oncogenic signaling, which could depend on
progranulin-mediated crosstalks between multiple RTKs depending on cellular context.
6. Conclusions and Future Perspectives
Growing evidence supports a critical role for progranulin in cancer, both as a pro-
oncogenic molecule and a theragnostic biomarker, thereby making it an attractive target for
cancer therapy. Recent studies suggest that progranulin mechanisms of action are highly
context dependent and involve the activation of multiple RTKs and downstream signaling
pathways. This aspect of progranulin activity suggests that progranulin-based therapeutic
approaches might have to be tailored to specific tumor contexts and that multimodal
approaches might be required to target the multiple signaling pathways that are activated
by progranulin.
Author Contributions:
Conceptualization, E.V. and A.M.; Writing—original draft preparation, E.V.
and A.M.; writing—review and editing, E.V., G.D., R.B.D., V.R., E.S., A.B., M.V., R.V.I., A.G. and
A.M.; supervision, A.M. and A.G.; funding acquisition, A.G. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by the Sbarro Health Research Organization (www.shro.org).
Acknowledgments:
We thank https://www.somersault1824.com/ (accessed on 26 February 2023)
for providing figure building blocks. We apologize for all the important works in the field we were
unable to cite.
Conflicts of Interest: The authors declare no conflict of interest.

Cancers 2023,15, 1706 14 of 21
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