A leading cause of female mortality is the development and dissemination of aggressive breast cancer. The bidirectional communication between the tumor microenvironment and neoplastic cells is key for promoting and fostering unchecked tumorigenic development, aberrant neovascularization, and widespread metastasis. Therefore, fully decoding the molecular messages embedded within the tumor stroma is advantageous and conducive for predicting tumor progression and metastasis. Our central hypothesis is that decorin, a secreted small leucine-rich proteoglycan, acts as a pan-receptor tyrosine kinase antagonist acting as a guardian from the matrix. This working hypothesis is based on several key observations, all generated under the auspices of this grant. We discovered: [a] Soluble decorin antagonizes Met receptor activity and downregulates ?-catenin and Myc, with a concomitant inhibition of angiogenesis by suppressing HIF-1??and VEGFA, [b] Systemic delivery of decorin causes remarkable genotypic changes in the stroma of orthotopic breast carcinoma xenografts, and we identified a novel gene, Peg3, as a decorin-induced tumor suppressor, [c] Decorin induces endothelial cell autophagy via Peg3 and AMPK?, an energy sensor kinase implicated in oncostasis, [d] Employing a custom-designed digital PCR code-set, NanoString, revealed an unambiguous and differential autophagic transcriptomic signature inducible by decorin, [e] The decorin-inducible gene mitostatin causes mitophagy in triple-negative breast carcinoma cells via PGC-1?? [f] Decorin acts as a partial VEGFR2 agonist and induces TFEB, a transcription factor regulating lysosomal biogenesis and autophagic flux, and [f] Decorin induces mitostatin to physically associate with Parkin, an E3 ubiquitin ligase that plays key roles in mitochondrial turnover. These discoveries posit decorin as a soluble pro-autophagic cue that triggers a highly conserved catabolic program manifesting in anti-angiogenic and oncostatic activity. We hypothesize that decorin would dually act on the tumor vasculature, by inducing unrestrained autophagy, and on the tumor proper, by suppressing Met and evoking excessive mitophagy. Based on these discoveries, we plan to: [1] Decipher the mechanism of action of decorin-evoked endothelial cell autophagy. [2] Elucidate the mechanism underlying decorin-evoked mitophagy in breast carcinoma cells via mitostatin, and [3] Generate novel mouse models of tumor angiogenesis and tumor cell mitophagy, and investigate the role of decorin, Peg3 and mitostatin in primary and metastastic breast carcinomas. Collectively, these studies will enable us to translate findings procured with novel mouse models of inducing pro-autophagic events within the breast microenvironment into clinically relevant therapeutic paradigms. The discovery of dual decorin activity concurrently evoking endothelial autophagy and tumor cell mitophagy opens new possibilities for anti-angiogenic and anti-oncogenic therapies. Thus, our studies catalyze the development of new therapeutics that concurrently targets the tumor stroma and the cancer cells.

Public Health Relevance

We have discovered that decorin, a soluble proteoglycan with tumor suppressor activity, induces excessive autophagy or self-eating in the cells lining cancer vessels, and concurrently evokes intracellular degradation of mitochondria, major organelles that produce energy required for breast carcinoma cells to proliferate and invade tissues. This dual activity of decorin, targeting both the tumor stroma and the tumor proper, will be investigated utilizing state-of-the-art molecular methodologies combined with highly-innovative mouse models of primary and metastatic mammary carcinomas. We expect that our studies will uncover novel avenues of research targeting both primary and metastatic mammary carcinomas using decorin as valuable treatment against this devastating disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Hildesheim, Jeffrey
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Thomas Jefferson University
Schools of Medicine
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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
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
Buraschi, Simone; Neill, Thomas; Iozzo, Renato V (2017) Decorin is a devouring proteoglycan: Remodeling of intracellular catabolism via autophagy and mitophagy. Matrix Biol :
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

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