Grant: Operating Grant

Colorectal cancer (CRC) is the second cause of cancer-related dead in Canada. Nonetheless, the lack of appropriate diagnostic and prognostic markers and resistance to treatments are still hallmarks of CRC. We know from previous studies that the P2Y6 receptor is located in the proliferative compartment of colon. This particular localization suggests that P2Y6 might be involved in the proliferation of intestinal epithelial cells. Hence, recent results are supporting the pro-proliferative role of P2Y6 on a subtype of cancerous colon epithelial cells. In fact, cells harboring mutation in tumor suppressor genes APC and TP53 display enhanced expression of P2Y6 when compared to cells not having these mutations. The HYPOTHESIS supporting this project is that the up-regulation of P2Y6 expression and activity promotes carcinogenesis by conferring a growth advantage to cancerous intestinal cells. We will prove the hypothesis through two aims. AIM 1: To determine the molecular modifications regulating P2Y6 expression and activity in epithelial colorectal cancer cells. AIM 2: To characterize P2Y6 receptor functions in the promotion of colorectal carcinogenesis. The plan experiments will use cellular and molecular biology techniques applied to cell and CRC-related animal models. We will than translate our results to patient by using human biopsies of CRC tumors. The expected outcomes will show that: 1) P2Y6 expression increases in cancer cells with mutation in tumor suppressor genes APC and TP53. 2) That cells expressing high levels of P2Y6 are less sensitive to cancer treatments as this receptor favor tumor growth. From a clinical point-of-view, we expect: 1) that P2Y6 expression levels might be use as biochemical indicator to modulate CRC treatments. 2) To target P2Y6 with blocking molecules to sensitize intestinal cancer cells to chemotherapeutic agents in order to block colorectal carcinogenesis.