Examining the role of a novel stromal cell protein CD362/Syndecan-2 in the breast tumour microenvironment.
Loftus, Paul Gerard
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Tumour-associated stromal cells play a key role in initiating and sustaining tumour growth, metastasis, immune control and chemo-resistance. Thus, identifying stromal proteins that contribute to carcinogenesis may open new therapeutic paradigms. We have identified Syndecan-2 (SDC2/CD362) as a novel antigen for identification of stromal cells (SC) from breast cancer tissue. SDC2 is a cell surface heparan sulfate proteoglycan that has been shown to be elevated in breast and other cancers. We demonstrate that SDC2+ SC and SDC2+ epithelial cells are present in murine and human breast tumours by flow cytometry and that levels of SDC2 are elevated in the sera of triple negative breast cancer patients. ShRNA knockdown of SDC2 in MDA-MB-231 triple negative breast cancer cells (BCC) inhibits TGFβ-induced markers of epithelial to mesenchymal transition (EMT) and BCC migration. Knocking down SDC2 in primary human tumour-derived SC also limits TGFβ signalling, inhibiting the ability of SC to suppress T cell proliferation. Our data indicates that modulation of SDC2 in human tumour-derived SC significantly alters tumour carcinogenesis in a xenograft orthotopic breast cancer model. Thus we hypothesise SDC2 is a functional protein within the tumour microenvironment (TME) promoting tumour growth, migration and immune-suppression; and therefore therapeutic targeting of SDC2 may yield a novel treatment for breast cancer. To that end, we generated novel SDC2 peptides that inhibit the clonogenic survival, migration and TGFβ-induced EMT of BCC in vitro. In addition, SDC2 peptides inhibit the immune suppressive properties of SC and this correlates with a decrease in expression of immune suppressive mediators CXCR4 and PD-L1. Importantly, SDC2 peptides display anti-tumourigenic properties in vivo as overexpression of a SDC2 peptide in SC within the TME reduces breast carcinogenesis in both xenograft and syngeneic mouse models.