Abstract
The complex interplay between malignant cells and the cellular and molecular components of the tumor stroma is a key aspect of cancer growth and development. These tumor-host interactions are often affected by soluble bioactive molecules such as proteoglycans. Decorin, an archetypical small leucine-rich proteoglycan primarily expressed by stromal cells, affects cancer growth in its soluble form by interacting with several receptor tyrosine kinases (RTK). Overall, decorin leads to a context-dependent and protracted cessation of oncogenic RTK activity by attenuating their ability to drive a pro-survival program and to sustain a pro-angiogenic network. Through an unbiased transcriptomic analysis using deep RNAseq, we discovered that decorin downregulated a cluster of tumor-associated genes involved in lymphatic vessel development when systemically delivered to mice harboring breast carcinoma allografts. We found that Lyve1 and Podoplanin, two established markers of lymphatic vessels, were markedly suppressed at both the mRNA and protein levels and this suppression correlated with a significant reduction in tumor lymphatic vessels. We further discovered that soluble decorin, but not its homologous proteoglycan biglycan, inhibited lymphatic vessel sprouting in an ex vivo 3D model of lymphangiogenesis. Mechanistically, we found that decorin interacted with VEGFR3, the main lymphatic RTK, and its activity was required for the decorin-mediated block of lymphangiogenesis. Finally, we discovered that Lyve1 was in part degraded via decorin-evoked autophagy in a nutrient- and energy-independent manner. These findings implicate decorin as a new biological factor with anti-lymphangiogenic activity and provide a potential therapeutic agent for curtailing breast cancer growth and metastasis.