Tumor progression and metastasis are in part driven by proliferating microvessels that provide oxygen and nutrients to the growing cancer cells. Angiogenic vessels exert an instructive role as a vascular niche by providing paracrine and angiocrine modes of regulation which include secretion and processing of various growth factors and extracellular matrix constituents that in turn influence tumor and endothelial cells in a bidirectional way. Perlecan, a major heparan sulfate proteoglycan secreted by endothelial cells, is a complex regulator of vascular biology and tumor angiogenesis. Perlecan shows a clear functional dichotomy. The parent proteoglycan is pro-angiogenic by acting as a co-receptor for FGF2 and VEGFA via the N-terminal heparin sulfate chains. In contrast, the C-terminal portion of perlecan, named endorepellin, is anti-angiogenic. We have recently discovered that endorepellin binds with high affinity to both ?2?1 integrin and VEGFR2. This dual receptor binding induces co-internalization and physical downregulation of both receptors, activation of SHP-1 and attenuation of VEGFA transcription. These findings provide a new paradigm for the activity of an anti-angiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both ?2?1 integrin and VEGFR2. Our long-term objectives are to expand these observations by investigating the binding mode of endorepellin and its various LG modules to the ectodomain of VEGFR2, and decipher the downstream signaling pathway evoked by this natural antagonist of two major angiogenic receptors. Specifically we plan to:  Investigate the precise mode through which endorepellin and its LG modules bind to the ectodomain of VEGFR2.  Decipher the downstream signaling pathways evoked by endorepellin on vascular endothelial cells, and  Generate novel mouse models of tumorigenesis where endorepellin and perlecan are conditionally overexpressed or ablated, respectively, in the endothelia of growing tumors. The expected results should generate a coherent and unified mode of action for endorepellin, identify new target proteins involved in its signaling pathway which could be potential novel targets for anti-angiogenesis therapy, and establish its in vivo role as an anti-angiogenic factor using unambiguous gain- and loss-of-function experiments through endothelial cell-specific gene targeting.
This proposal is based on the discovery that endorepellin, a fragment of perlecan, exhibits potent angiostatic activity via a dual receptor antagonism to regulate angiogenesis. Deciphering the precise mode of action for endorepellin and being able to directly target established tumor vasculature would be of substantial benefit to future anti-angiogenic therapies, not only for cancer but also for other pathologies where angiogenesis plays a pivotal role.
|Gubbiotti, Maria A; Seifert, Erin; Rodeck, Ulrich et al. (2018) Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin. J Biol Chem 293:16940-16950|
|Karamanos, Nikos K; Theocharis, Achilleas D; Neill, Thomas et al. (2018) Matrix modeling and remodeling: A biological interplay regulating tissue homeostasis and diseases. Matrix Biol :|
|Neill, Thomas; Andreuzzi, Eva; Wang, Zi-Xuan et al. (2018) Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature. J Biol Chem 293:12137-12148|
|Iozzo, Renato V; Gubbiotti, Maria A (2018) Extracellular matrix: The driving force of mammalian diseases. Matrix Biol 71-72:1-9|
|Torres, Annabel; Gubbiotti, Maria A; Iozzo, Renato V (2017) Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis. J Biol Chem 292:5055-5069|
|Gubbiotti, Maria A; Neill, Thomas; Iozzo, Renato V (2017) A current view of perlecan in physiology and pathology: A mosaic of functions. Matrix Biol 57-58:285-298|
|Neill, Thomas; Sharpe, Catherine; Owens, Rick T et al. (2017) Decorin-evoked paternally expressed gene 3 (PEG3) is an upstream regulator of the transcription factor EB (TFEB) in endothelial cell autophagy. J Biol Chem 292:16211-16220|
|Pozzi, Ambra; Yurchenco, Peter D; Iozzo, Renato V (2017) The nature and biology of basement membranes. Matrix Biol 57-58:1-11|
|DeRita, Rachel M; Zerlanko, Brad; Singh, Amrita et al. (2017) c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes. J Cell Biochem 118:66-73|
|Schaefer, Liliana; Tredup, Claudia; Gubbiotti, Maria A et al. (2017) Proteoglycan neofunctions: regulation of inflammation and autophagy in cancer biology. FEBS J 284:10-26|
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