Ugo Cavallaro

IEO - Istituto Europeo di Oncologia | IEO · Unit of Gynecological Oncology Research

Biomedical applications of molecules that are able to modulate β-adrenergic signaling have become increasingly attractive over the last decade, revealing that β-adrenergic receptors (β-ARs) are key targets for a plethora of therapeutic interventions, including cancer. Despite successes in β-AR drug discovery, identification of β-AR ligands that are...

Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy worldwide due to a late diagnosis caused by the lack of specific symptoms and rapid dissemination into the peritoneal cavity. The standard of care for OC treatment is surgical cytoreduction followed by platinum-based chemotherapy. While a response to this frontline treatment...

Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer...

Background: Individual serum biomarkers are neither adequately sensitive nor specific for use in screening the general population for ovarian cancer. The purpose of this study was to develop a multiprotein classifier to detect the early stages of ovarian cancer, when it is most treatable. Methods: The Olink Proseek Multiplex Oncology II panel wa...

Cell adhesion molecule L1 is a cell surface glycoprotein that promotes neuronal cell migration, fosters regeneration after spinal cord injury and ameliorates the consequences of neuronal degeneration in mouse and zebrafish models. Counter-indicative features of L1 were found in tumor progression: the more L1 is expressed, the more tumor cells migra...

High‐grade serous ovarian carcinoma (HGSOC) is a highly aggressive and intractable neoplasm, mainly because of its rapid dissemination into the abdominal cavity, a process that is favored by tumor‐associated peritoneal ascites. The precise molecular alterations involved in HGSOC onset and progression remain largely unknown due to the high biologica...

Background Cancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been el...

Poly ADP-ribose polymerase inhibitors (PARPi) have transformed ovarian cancer (OC) treatment, primarily for tumours deficient in homologous recombination repair. Combining VEGF-signalling inhibitors with PARPi has enhanced clinical benefit in OC. To study drivers of efficacy when combining PARP inhibition and VEGF-signalling, a cohort of patient-de...

High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients’ metastatic as...

Background High-grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The remaining uncertainty on its originating tissue has hampered the discovery of molecular oncogenic pathways and the development of effective therapies. Methods We used an approach based on the retention in tumors of a DNA methylation trace (OriPrint) that dis...

Rationale: Intercellular tight junctions are crucial for correct regulation of the endothelial barrier. Their composition and integrity are affected in pathological contexts, such as inflammation and tumour growth. 'Junctional adhesion molecule-A' (JAM-A) is a transmembrane component of tight junctions with a role in maintenance of endothelial barr...

Ovarian cancer stem cells (OCSC) are believed to fuel tumor metastasis, recurrence, and chemoresistance. Therefore, understanding the molecular players involved in OCSC function represents an urgent need towards the design of innovative and more efficacious treatments of this neoplasm. Our molecular profiling of primary OCSC isolated from high-grad...

L1 cell adhesion molecule (L1CAM) is aberrantly expressed in several tumor types where it is causally linked to malignancy and therapy resistance, acting also as a poor prognosis factor. Accordingly, several approaches have been developed to interfere with L1CAM function or to deliver cytotoxic agents to L1CAM-expressing tumors. Metastatic dissemin...

Many biological and clinical features of ovarian cancer (OC) support the notion that the disease is driven by a subpopulation of self-renewing cancer stem cells (CSC) that are able to generate the entire progeny of short-lived, differentiated and heterogeneous cells that compose the tumor bulk. Ovarian cancer stem cells (OCSC), in particular, have...

Introduction Ovarian cancer (OC) is the most lethal gynaecological malignancy due to the lack of peculiar symptoms in its early phase (Bowtell, 2010). OC often relapses as a chemoresistant disease within 3 years after surgical debulking (Lengyel, 2010; Sun et al, 2007). These pathological hallmarks raised the hypothesis that OC is a cancer-stem cel...

Introduction Ovarian cancer (OC) is the most lethal gynaecological malignancy due to the lack of peculiar symptoms in its early phase (Bowtell, 2010). OC often relapses as a chemoresistant disease within 3 years after surgical debulking (Lengyel, 2010; Sun et al, 2007). These pathological hallmarks raised the hypothesis that OC is a cancer-stem cel...

e17063 Background: The still persistent uncertainty in the identification of the cell of origin of high grade serous ovarian cancer (HGSOC), with two candidate originating tissues identified in the distal tract of the fallopian tube (FI) and the surface epithelium of the ovary (OSE), has hampered the identification of clinically relevant molecular...

The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to L1CAM pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in...

High grade serous ovarian cancer (HGSOC) is a major unmet need in oncology. The persistent uncertainty on its originating tissue has contributed to hamper the discovery of oncogenic pathways and effective therapies. Here we define the DNA methylation print that distinguishes the human fimbrial (FI) and ovarian surface epithelia (OSE) and develop a...

High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients' ascites, esta...

Both fibroblast growth factor-2 (FGF2) and neural cell adhesion molecule (NCAM) trigger FGF receptor 1 (FGFR1) signaling; however, they induce remarkably distinct receptor trafficking and cellular responses. The molecular basis of such a dichotomy and the role of distinct types of ligand-receptor interaction remain elusive. Number of molecules and...

Introduction Ovarian cancer (OC) is the most lethal gynaecological malignancy due to the lack of peculiar symptoms during its onset. Moreover, OC often relapses as a chemoresistant disease within 1–2 years after surgical debulking. These pathological hallmarks raised the hypothesis that OC is a cancer-stem cell (CSC)-driven disease. Indeed, a ‘stem...

A xenobank of patient-derived (PDX) ovarian tumor samples has been established consisting of tumors with different sensitivity to cisplatin (DDP), from very responsive to resistant. As the DNA repair pathway is an important driver in tumor response to DDP, we analyzed the mRNA expression of 20 genes involved in the nucleotide excision repair, fanco...

Cancer-initiating cells (CICs) have been implicated in tumor development and aggressiveness. In ovarian carcinoma (OC), CICs drive tumor formation, dissemination, and recurrence, as well as drug resistance, thus accounting for the high death-to-incidence ratio of this neoplasm. However, the molecular mechanisms that underlie such a pathogenic role...

Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of...

Table S3. Upstream Regulator Analysis of Genes Differentially Expressed in HGSOC-Derived Spheres

Table S4. Genes Co-regulated with NT5E/CD73 in OC Samples: Data Obtained from TCGA Database

Rationale: The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Exp...

Our understanding of the molecular determinants of cancer is still inadequate because of cancer heterogeneity. Here, using epithelial ovarian cancer (EOC) as a model system, we analyzed a minute amount of patient-derived epithelial cells from either healthy or cancerous tissues by single-shot mass-spectrometry-based phosphoproteomics. Using a multi...

Table S4. List of the 792 Differentially Expressed Phosphorylated Sites in Patient-Derived Cells; Related to Figure 4 Sequence window, phosphorylated amino acid residue, the cluster letter, the p value after the analysis with the LIMMA Bioconductor package in R are reported for all the samples. P-values < 0.05 and p-values >=0.05 are color-coded i...

Table S5. List of the Phosphorylated Proteins Belonging to the GO Term Splicesosome; Related to Figures 3 and 4 Sequence window, phosphorylated amino acid residue, the biological function, the significance in the PCA analysis or after comparison with the proteome analysis, the kinase motif, the function according to(Papasaikas et al., 2015) are re...

Table S8. List of the Identified Phosphorylated Sites in OVCAR3; Related to Figure 5 Sequence window, phosphorylated amino acid residue, the log10 intensity of all phosphorylated sites with localization probabilities higher than 0.75 (class I), motif analysis, the GO terms, biological functions, the presence in patient-derived cells, the name of t...

Table S1. List of Patient-Derived Samples Used in This Study; Related to Figures 1, 2, 4, and 5 and Experimental Procedures N: arbitrary and sequential numbers. Samples 1, 2, and 4 have been separated in two technical replicates. Sample: samples derived from normal FTE (FTE), normal ovarian surface epithelium (OSE) or from ascites of patients with...

Table S2. List of All the Identified Proteins in Patient-Derived Cells; Related to Figures 1 and 2 Of the 5561 identified proteins we filtered proteins identified with less than two peptides and with poor sequence coverage (less than 5%) before further analysis (4457 proteins). MUC16/CA125 and PRSS8 are identified by an asterisk. Proteins in red w...

Table S3. List of the Identified Phosphorylated Sites in Patient-Derived Cells; Related to Figures 1, 3, 4, and 5 Sequence window, phosphorylated amino acid residue, the log10 intensity of all phosphorylated sites with localization probabilities higher than 0.75 (class I), the normalized mean, the GO terms, the significant p value after the analys...

Table S7. List of Known POLR2A-Associated Proteins Identified in Patient-Derived Cells; Related to Figure 4

The cancer stem cell (CSC) model proposes that tumor development and progression are fueled and sustained by undifferentiated cancer cells, endowed with self-renewal and tumor-initiating capacity. Ovarian carcinoma, based on its biological features and clinical evolution, appears as a prototypical example of CSC-driven disease. Indeed, ovarian canc...

Elucidating the molecular basis of tumor metastasis is pivotal for eradicating cancer-related mortality. Triple-negative breast cancer (TNBC) encompasses a class of aggressive tumors characterized by high rates of recurrence and metastasis, as well as poor overall survival. Here, we find that the promyelocytic leukemia protein PML exerts a prometas...

Angiogenesis, the formation of new vessels, is a key step in the development, invasion, and dissemination of solid tumors and, therefore, represents a viable target in the context of antitumor therapy. Indeed, antiangiogenic approaches have given promising results in preclinical models and entered the clinical practice. However, in patients, the re...

Myosin VI functions in endocytosis and cell motility. Alternative splicing of myosin VI mRNA generates two distinct isoform types, myosin VIshort and myosin VIlong, which differ in the C-terminal region. Their physiological and pathological roles remain unknown. Here we identified an isoform-specific regulatory helix, named the α2-linker, that defi...

Ovarian cancer (OC) represents an outstanding clinical challenge due to its high mortality rate, tumor relapse and chemoresistance. The identification of novel targets and strategies for the treatment of OC is clearly an unmet need in clinical oncology. In this context, drugs that interfere with tumor neovascularization have shown some promising re...

Recent data suggest that drug resistance and/or disease recurrence in ovarian cancer (OC) are driven by a subpopulation of cells in human tumors with stem-like characteristics (cancer stem cells, CSCs). CSCs are defined as a small subpopulation of cells within the tumor bulk that possess the capacity, on one hand, to self-renew and, on the other ha...

Epithelial ovarian cancer (EOC) is diagnosed in more than 70% of the cases in advanced FIGO stages which renders EOC the most deadly gynecologic cancer. Up to date there are no specific symptoms and no screening tests for general population or for patients at risk. The development of early diagnostic tools that will improve clinical outcome and dif...

The neural adhesion molecule L1 is involved in development and plasticity of the nervous system. We recently reported aberrant expression of L1 in the vasculature of various human tumor types. Genetic and functional inactivation of endothelial L1 in a mouse tumor model resulted in decreased tumor angiogenesis and promoted vascular normalization. Th...

Epithelial Ovarian Cancer (OC) is one of the leading causes of death for women, and no significant therapeutic progress has been made in the last decades. Recent data suggest that one of the mechanisms accounting for resistant and/or relapsing disease is a subpopulation of cells in human tumors with stem-like characteristics (cancer stem cells, CSC...

We recently identified a novel role for the L1 transmembrane glycoprotein (also known as L1CAM or CD171) in the regulation of tumor angiogenesis and vessels stabilization. L1 overexpression in cultured endothelial cells of the lung (luECs) exerted a pleiotropic effect in that it regulated proliferation, migration, tubulogenesis, vascular permeabili...

The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of actio...

While tumor blood vessels share many characteristics with normal vasculature, they also exhibit morphological and functional aberrancies. For example, the neural adhesion molecule L1, which mediates neurite outgrowth, fasciculation, and pathfinding, is expressed on tumor vasculature. Here, using an orthotopic mouse model of pancreatic carcinoma, we...

The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferation, whereas FGF-10 promotes receptor recycling and ce...

Sprouting of angiogenic perivascular cells is thought to be highly dependent upon autocrine and paracrine growth factor stimulation. Accordingly, we report that corneal angiogenesis induced by ectopic FGF implantation is strongly impaired in NG2/CSPG4 proteoglycan (PG) null mice known to harbour a putative deficit in pericyte proliferation/mobiliza...

A murine endothelial cell line was recently established from microvessels that had invaded a subcutaneous sponge implant (Dong, Q. G.; Bernasconi, S.; Lostaglio, S., et al. Arterioscl. Thromb. Vasc. Biol. 17:1599–1604; 1997). From these sponge-induced endothelial (SIE) cells, we have isolated two subpopulations endowed with different phenotypic pro...

Endothelial cells (ECs) express 2 members of the cadherin family, VE and N-cadherin. Although VE-cadherin induces EC homotypic adhesion, N-cadherin function in ECs remains largely unknown. EC-specific inactivation of either VE or N-cadherin leads to early fetal lethality suggesting that these cadherins play a nonredundant role in vascular developme...

Neural cell adhesion molecule (NCAM) is a nonconventional ligand for fibroblast growth factor receptor-1 (FGFR1). NCAM exerts a peculiar control on the intracellular trafficking of FGFR1, resulting in a specific cellular response, which is remarkably different from that elicited by the canonical ligand FGF2 (Francavilla et al., JCB 2009).We studied...