Carl-Henrik Heldin

Carl-Henrik Heldin
Ludwig Institute for Cancer Research Australia

About

758
Publications
58,309
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93,899
Citations
Citations since 2017
61 Research Items
14354 Citations
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201720182019202020212022202305001,0001,5002,0002,500
201720182019202020212022202305001,0001,5002,0002,500
201720182019202020212022202305001,0001,5002,0002,500

Publications

Publications (758)
Article
The liver kinase B1 (LKB1) controls cellular metabolism and cell polarity across species. We previously established a mechanism for negative regulation of transforming growth factor β (TGFβ) signaling by LKB1. The impact of this mechanism in the context of epithelial polarity and morphogenesis remains unknown. After demonstrating that human mammary...
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In the present study, we show that the inhibitor of the apoptosis-stimulating protein of p53 (iASPP) physically interacts with the hyaluronan receptor CD44 in normal and transformed cells. We noticed that the CD44 standard isoform (CD44s), but not the variant isoform (CD44v), bound to iASPP via the ankyrin-binding domain in CD44s. The formation of...
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Breast cancer is a common cancer in women. Breast cancer cells synthesize large amounts of hyaluronan to assist their proliferation, survival, migration and invasion. Accumulation of hyaluronan and overexpression of its receptor CD44 and hyaluronidase TMEM2 in breast tumors correlate with tumor progression and reduced overall survival of patients....
Article
Transforming growth factor–β (TGF-β) signaling has important roles during embryonic development and in tissue homeostasis. TGF-β ligands exert cellular effects by binding to type I (TβRI) and type II (TβRII) receptors and inducing both SMAD-dependent and SMAD-independent intracellular signaling pathways, the latter of which includes the activation...
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The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGFβ. Th...
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Glioblastoma multiforme (GBM) is a lethal brain tumor, characterized by enhanced proliferation and invasion, as well as increased vascularization and chemoresistance. The expression of the hyaluronan receptor CD44 has been shown to correlate with GBM progression and poor prognosis. Here, we sought to elucidate the molecular mechanisms by which CD44...
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Background Transforming growth factor β (TGFβ) is overexpressed in several advanced cancer types and promotes tumor progression. We have reported that the intracellular domain (ICD) of TGFβ receptor (TβR) I is cleaved by proteolytic enzymes in cancer cells, and then translocated to the nucleus in a manner dependent on the endosomal adaptor proteins...
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Complexity in mechanisms that drive cancer development and progression is exemplified by the transforming growth factor β (TGF-β) signaling pathway, which suppresses early-stage hyperplasia, yet assists aggressive tumors to achieve metastasis. Of note, several molecules, including mRNAs, non-coding RNAs, and proteins known to be associated with the...
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Transforming growth factor β (TGFβ) induces epithelial‐mesenchymal transition (EMT), which correlates with stemness and invasiveness. Mesenchymal‐epithelial transition (MET) is induced by TGFβ withdrawal and correlates with metastatic colonization. Whether TGFβ promotes stemness and invasiveness simultaneously via EMT remains unclear. We establishe...
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Interaction of platelet-derived growth factor (PDGF) isoforms with their receptors results in activation and internalization of receptors, with a concomitant activation of downstream signalling pathways. Ubiquitination of PDGFRs serves as a mark to direct the internalization and sorting of the receptors. By overexpressing a panel of deubiquitinatin...
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Glioblastoma (GBM) is a brain malignancy characterized by invasiveness to the surrounding brain tissue and by stem-like cells, which propagate the tumor and may also regulate invasiveness. During brain development, polarity proteins, such as Par3, regulate asymmetric cell division of neuro-glial progenitors and neurite motility. We, therefore, stud...
Article
We previously reported that bone morphogenetic protein (BMP) signaling promotes tumorigenesis in gynecologic cancer cells. BMP2 enhances proliferation of ovarian and endometrial cancer cells via c-KIT induction, and triggers epithelial-mesenchymal transition (EMT) by SNAIL and/or SLUG induction, leading to increased cell migration. However, the dow...
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The role of liver kinase B1 (LKB1) in glioblastoma (GBM) development remains poorly understood. LKB1 may regulate GBM cell metabolism and has been suggested to promote glioma invasiveness. After analyzing LKB1 expression in GBM patient mRNA databases and in tumor tissue via multiparametric immunohistochemistry, we observed that LKB1 was localized a...
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The effects of bone morphogenetic proteins (BMPs), members of the transforming growth factor-β (TGF-β) family, in endometrial cancer (EC) have yet to be determined. In this study, we analyzed the TCGA and MSK-IMPACT datasets and investigated the effects of BMP2 and of TWSG1, a BMP antagonist, on Ishikawa EC cells. Frequent ACVR1 mutations and high...
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Glioma‐initiating cells (GICs), a major source of glioblastoma recurrence, are characterized by the expression of neural stem cell markers and the ability to grow by forming non‐adherent spheres under serum‐free conditions. Bone morphogenetic proteins (BMPs), members of the transforming growth factor‐β family, induce differentiation of GICs and sup...
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Activation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier...
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The hyaluronan receptor CD44 can undergo proteolytic cleavage in two steps, leading to the release of its intracellular domain; this domain is translocated to the nucleus, where it affects the transcription of target genes. We report that CD44 cleavage in A549 lung cancer cells and other cells is promoted by transforming growth factor-beta (TGFβ) i...
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BMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in...
Article
Transforming growth factor β (TGF-β) enhances migration and invasion of cancer cells, causing life-threatening metastasis. Smad7 expression is induced by TGF-β to control TGF-β signaling in a negative feedback manner. Here we report an additional function of Smad7, i.e., to enhance TGF-β induction of c-Jun and HDAC6 via binding to their regulatory...
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Transforming growth factor β (TGF-β) enhances migration and invasion of cancer cells, causing life-threatening metastasis. Smad7 expression is induced by TGF-β to control TGF-β signaling in a negative feedback manner. Here we report an additional function of Smad7, i.e., to enhance TGF-β induction of c-Jun and HDAC6 via binding to their regulatory...
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Platelet-derived growth factor B (PDGFB) plays a crucial role in recruitment of PDGF receptor β–positive pericytes to blood vessels. The endothelium is an essential source of PDGFB in this process. Platelets constitute a major reservoir of PDGFB and are continuously activated in the tumor microenvironment, exposing tumors to the plethora of growth...
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Bone morphogenetic proteins (BMPs) are secreted cytokines that control the fate and function of many different cell types. They exert their cellular responses via heteromeric complexes of specific BMP type I and type II serine/threonine kinase receptors, e.g. BMPRIA and BMPRII. Three type II and four type I receptors, also termed activin receptor-l...
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Activator protein (AP)-1 transcription factors are essential elements of the pro-oncogenic functions of transforming growth factor-β (TGFβ)-SMAD signaling. Here we show that in multiple HER2+ and/or EGFR+ breast cancer cell lines these AP-1-dependent tumorigenic properties of TGFβ critically rely on epidermal growth factor receptor (EGFR) activatio...
Article
PDGF-BB/PDGFRβ signaling plays an important role during vascularization by mediating pericyte recruitment to the vasculature, promoting the integrity and function of vessels. Until now it has not been possible to assess the specific role of PDGFRβ signaling in tumor progression and angiogenesis due to lack of appropriate animal models and molecular...
Article
Hyaluronan and its major receptor CD44 are ubiquitously distributed. They have important structural as well as signaling roles, regulating tissue homeostasis, and their expression levels are tightly regulated. In addition to signaling initiated by the interaction of the intracellular domain of CD44 with cytoplasmic signaling molecules, CD44 has imp...
Article
Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such d...
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Background: A main pathological feature of severe dengue virus infection is endothelial hyper-permeability. The dengue virus nonstructural protein 1 (NS1) has been implicated in the vascular leakage that characterizes severe dengue virus infection, however, the molecular mechanisms involved are not known. Methods: A cohort of 250 dengue patients...
Article
Dual specificity phosphatase (DUSP) 4 has been described as a negative regulator of MAP kinase signaling, in particular for the ERK1/2 and JNK pathways. We found that DUSP4 expression was upregulated in response to prolonged platelet-derived growth factor (PDGF)-BB stimulation. The PDGF-BB-induced DUSP4 expression was dependent on ERK1/2, STAT3 and...
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Molecular processes involving lncRNAs regulate cell function. By applying transcriptomics, we identify lncRNAs whose expression is regulated by transforming growth factor β (TGF-β). Upon silencing individual lncRNAs, we identify several that regulate TGF-β signaling. Among these lncRNAs, TGFB2-antisense RNA1 (TGFB2-AS1) is induced by TGF-β through...
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Transforming growth factor β (TGFβ) is deposited in the extracellular space of diverse tissues. Resident fibroblasts respond to TGFβ and undergo myofibroblastic differentiation during tissue wound healing and cancer progression. Cancer-associated fibroblasts (CAFs) communicate with tumor cells during cancer progression, under the guidance of TGFβ s...
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TGFβ signaling via SMAD proteins and protein kinase pathways up- or down-regulates the expression of many genes and thus affects physiological processes, such as differentiation, migration, cell cycle arrest, and apoptosis during developmental or adult tissue homeostasis. We here report that NUAK family kinase 1 (NUAK1) and NUAK2 are two TGFβ targe...
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The mammalian target of rapamycin (mTOR) pathway is commonly activated in human cancers. The activity of mTOR complex 1 (mTORC1) signaling is supported by the intracellular positioning of cellular compartments and vesicle trafficking, regulated by Rab GTPases. Here we showed that tuftelin 1 (TUFT1) was involved in the activation of mTORC1 through m...
Article
The glycosaminoglycan hyaluronan has a crucial role in tissue organization and cell signaling. Hyaluronan accumulates in conjunction with rapid tissue remodeling during embryogenesis, as well as in inflammatory conditions and cancer. We report a negative correlation between the expression of genes encoding hyaluronan synthase HAS2, its natural anti...
Data
Table S1. An Excel file including primary data from the ChIP‐Seq analysis.This file tabulates in an organized manner the raw data deposited in Array Express under accession number E‐MTAB‐5242. The data are organized as: chromosome number, peak start, peak end, MACS, peak score, gene start, gene end, gene name, transcribed strand and distance from t...
Data
Table S2. An Excel file presenting the primary data from the AmpliSeq analysis.This file tabulates in an organized manner the raw data deposited in Array Express under accession number E‐MTAB‐5244. The data are organized as: Gene name, Target ID, ENTREZ_GENE_ID, normalized expression values in triplicate samples of the mock C3 clone (up_242_1, up_2...
Article
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Translocation of full-length or fragments of receptors to the nucleus has been reported for several tyrosine kinase receptors. In this paper, we show that a fraction of full-length cell surface platelet-derived growth factor (PDGF) receptor β (PDGFRβ) accumulates in the nucleus at the chromatin and the nuclear matrix after ligand stimulation. Nucle...
Article
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Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor β (TGFβ) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the trans...
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Understanding the complexity of changes in differentiation and cell survival in hepatocellular carcinoma (HCC) is essential for the design of new diagnostic tools and therapeutic modalities. In this context, we have analyzed the crosstalk between transforming growth factor β (TGFβ) and liver X receptor α (LXRα) pathways. TGFβ is known to promote cy...
Article
Transforming growth factor β (TGFβ) family members signal via heterotetrameric complexes of type I (TβRI) and type II (TβRII) dual specificity kinase receptors. The availability of the receptors on the cell surface is controlled by several mechanisms. Newly synthesized TβRI and TβRII are delivered from the Golgi apparatus to the cell surface via se...
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It is well established that transforming growth factor-β (TGFβ) switches its function from being a tumor suppressor to a tumor promoter during the course of tumorigenesis, which involves both cell-intrinsic and environment-mediated mechanisms. We are interested in breast cancer cells, in which SMAD mutations are rare and interactions between SMAD a...
Article
Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, over-activity of PDGF signaling is associated with malignancies an...
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Transforming growth factor β (TGFβ) is a key regulator of epithelial-to-mesenchymal transition (EMT) during embryogenesis and in tumors. The effect of TGFβ, on ΕΜΤ, is conveyed by induction of the pro-invasive transcription factor Snail1. In this study, we report that TGFβ stimulates Snail1 sumoylation in aggressive prostate, breast and lung cancer...
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Transforming growth factor-β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3...
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Background Imatinib causes increased turnover of stromal collagen, reduces collagen fibril diameter, enhances extracellular fluid turnover and lowers interstitial fluid pressure (IFP) in the human colonic carcinoma KAT-4/HT-29 (KAT-4) xenograft model. Methods We compared the effects of imatinib on oxygen levels, vascular morphology and IFP in three...
Article
The human genome encodes 58 receptor tyrosine kinases (RTKs) that have important functions in the regulation of cell proliferation, survival, and migration during embryonal development, and for example, during wound healing in the adult. Based on their structural features the RTKs can be divided into 20 subfamilies, each of which binds a family of...
Article
The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context-dependent protein associations, as well as antagonism from mutant p53. ΔNp63 is an amino-terminal-truncated isof...
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Transforming growth factor β (TGF-β) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with othe...
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Plasticity in epithelial tissues relates to processes of embryonic development, tissue fibrosis and cancer progression. Pharmacological modulation of epithelial transitions during disease progression may thus be clinically useful. Using human keratinocytes and a robotic high-content imaging platform, we screened for chemical compounds that reverse...
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Transitory phenotypic changes such as the epithelial-mesenchymal transition (EMT) help embryonic cells to generate migratory descendants that populate new sites and establish the distinct tissues in the developing embryo. The mesenchymal descendants of diverse epithelia also participate in the wound healing response of adult tissues, and facilitate...
Article
Platelet-derived growth factor-BB (PDGF-BB) binds to its tyrosine kinase receptors (PDGFRs) and stimulates mitogenicity and survival of cells of mesenchymal origin. Activation of PDGFRs initiates a number of downstream signaling pathways, including phosphatidyl 3'-inositol kinase (PI3-kinase), phospholipase Cγ and MAP kinase pathways. In this repor...
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We previously established a mechanism of negative regulation of transforming growth factor β signaling mediated by the nuclear ADP-ribosylating enzyme poly-(ADP-ribose) polymerase 1 (PARP1) and the de-ribosylating enzyme poly-(ADP-ribose) glycohydrolase (PARG), which dynamically regulate ADP-ribosylation of Smad3 and Smad4, two central signaling pr...
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Protein ubiquitination controls protein stability and subcellular localization of tyrosine kinase receptors, hence affecting signaling both quantitatively and qualitatively. In this report, we demonstrate that after ligand stimulation the platelet-derived growth factor (PDGF) β-receptor (PDGFRβ) becomes ubiquitinated in a manner requiring both the...
Article
Communication between cells in a multicellular organism occurs by the production of ligands (proteins, peptides, fatty acids, steroids, gases, and other low-molecular-weight compounds) that are either secreted by cells or presented on their surface, and act on receptors on, or in, other target cells. Such signals control cell growth, migration, sur...