Transforming Growth Factor-β3: A Potential New Regulator of Heparan Sulfate Assembly and Functionality in Cancer

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Cancer is a major health problem being amongst the top three causes of death. The vast majority of cancer-related deaths occurs due to malignancy, the invasive and systemic spreading of tumor cells in different tissues. Cell invasion and spreading correspond with remodeling of the extracellular matrix and alterations of cell-cell and cell-matrix interactions. In this context, heparan sulfate proteoglycans present on all cell surfaces and in the extracellular matrix play a central role. Heparan sulfate proteoglycans known for their high structural diversity fine-tune physiology through interactions with a multitude of specific proteins and mediate key pathophysiological events during different aspects of tumor progression. Altered expression of enzymes involved in heparan sulfate proteoglycan biosynthesis and turnover have been reported for several cancer types. However, little is known about the regulatory factors that orchestrate the variable structural and functional properties of heparan sulfate proteoglycans. Transforming growth factor-ß (TGF-ß) is another key player in malignant disease. Depending on the cellular context, this family of regulatory cytokines can function as tumor suppressor by inhibiting cell proliferation in the premalignant state or as tumor promotor when the signaling pathway malfunctions, fostering tumor aggressiveness. Recently, a connection between TGF ß3 and heparan sulfate proteoglycan expression was discovered by Prof. Jeffrey Esko's group through a clustered regularly interspaced short palindromic repeat (CRISPR) and CRISPR-associated gene 9 (CRISPR-Cas9) genome wide screening using gene targeting in a human melanoma cell line. Interestingly, TGF-ß3 has been shown to modulate invasion and metastasis of several cancer types. We, therefore, propose an interdisciplinary research approach to examine the impact of TGF ß3 on heparan sulfate proteoglycan formation (i) by creating TGF-ß gene knockout mutants in melanoma and prostate cancer cells, (ii) by examining how altering the TGF ß3 / heparan sulfate proteoglycan axis impacts protein binding to heparan sulfate and tumor growth, and (iii) by investigating how inactivation of TGF-ß3 impacts heparan sulfate proteoglycan metabolism and the signaling pathways that mediate TGF-ß3 responses. The proposed project aims to identify the detailed molecular mechanism underlying heparan sulfate proteoglycan biosynthesis in response to TGF-ß3 expression. Insights from this study might foster a better understanding of disorders associated with altered heparan sulfate proteoglycan formation in cancer, which might in turn suggest novel ways to alter heparan sulfate proteoglycan composition and metastatic potential of tumor cells.