Centre for Research on Biomolecular Interactions presents Prof. Benjamin K. Tsang, Department of Obstetrics and Gynecology, University of Ottawa, Ottawa

Talk Title: "Chemoresistant Ovarian Cancer: Role of Exosome-mediated Cell-Cell Interactions in the Tumor Microenvironment"

Abstract: Ovarian Cancer (OVCA) is the most lethal gynecological cancer, due predominantly to late diagnosis, recurrence and chemoresistance. Although combined surgical debulking and chemotherapy is an important treatment strategy, chemoresistance remains a major challenge to successful long term therapeutic success. The responsiveness of cancer cells to chemotherapy is dependent on its microenvironment. Tumour-derived soluble factors and extracellular vesicles (e.g. exosomes) down-regulate T lymphocytes which influence the responsiveness of cancer cells to chemotherapy. Exosomes are membrane bound vesicles that transport biologically active proteins, nucleic acids and fatty acids to recipient cells to modulate their functions.
Plasma gelsolin (pGSN), a soluble isoform of GSN expressed from the same GSN gene, has been shown to interact with integrin; however, its role in chemoresistance is not known. We hypothesize that exosomes containing pGSN (Ex-pGSN) promotes OVCA cell survival through both autocrine and paracrine mechanisms, which transform chemosensitive cells to resistant counterparts and down-regulate the anti-tumor functions of T cells, respectively. pGSN is highly expressed in chemoresistant OVCA cells than in its chemosensitive counterparts. pGSN, secreted and transported via exosomes, up-regulates HIP-1α–mediated GSN expression in chemoresistant OVCA cells in an autocrine manner and confers cisplatin resistance in otherwise chemosensitive OVCA cells. Immunolocalization studies on high grade serious tumors indicate co-localization of pGSN with CD8+ T cells. Moreover, pGSN promotes recruitment and down-regulation of CD8+ T cell function by induction of apoptosis.
These findings support an important role of pGSN in conferring platinum resistance in OVCA through its autocrine actions and its paracrine immunosuppressive function in the ovarian tumor microenvironment (Supported by Canadian Institutes of Health Research).

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