Research Projects

Pancreatic cancer, the most common type called pancreatic ductal adenocarcinoma (PDAC), is a lethal malignancy often characterized by its rapidly metastatic nature and extremely low patient survival rate. Nucleoside analogs (NAs), such as gemcitabine, are the cornerstones of chemotherapy currently in clinical use for the treatment of PDAC. However, therapeutic resistance emerges due to critical factors such as an immunosuppressive tumor microenvironment (TME), epithelial-mesenchymal transition (EMT) and metastasis, which together contribute to cancer progression. Concentrative nucleoside transporter 3 (CNT3), also called solute carrier family 28, member 3 (SLC28A3), is a cell membrane-bound protein involved in the cellular uptake of endogenous nucleosides and NA anticancer drug, gemcitabine. Thus, CNT3 expression can improve the therapeutic efficacy of gemcitabine in cancers. Nonetheless, little known about the expression and role of CNT3 in cancer. Our preliminary investigation on CNT3 in pancreatic cancer suggests that the expression of this protein is downregulated in poorly differentiated pancreatic cancer patient tissues compared to the well-differentiated and adjacent normal tissues. Furthermore, TNMplot database search shows reduced Slc28a3 expression in metastatic pancreatic cancer patient tissues compared to the primary tumor and normal tissues. In addition, our data show loss of CNT3 expression increases cell proliferation in mouse pancreatic cancer KPC cells, while its overexpression inhibits cell proliferation and induces apoptosis, which suggests tumor suppressor role of this protein. Since EMT orchestrates the early stage events of metastasis and it supports chemoresistance properties of cancer cells by regulating expression of many chemosensitivity determinant genes, here, we hypothesize that EMT activation could be a plausible cause of loss of CNT3 in PDAC cells. Besides, cancer cells experiencing EMT secrete factors such as TGF-β, which elicits an immunosuppressive TME. We propose to investigate: (i) EMT as a mechanism for the downmodulation of CNT3, and the impact of loss of CNT3 on tumor immune evasion and cancer progression; (ii) identify and validate the molecular regulator(s) of loss of CNT3 expression in PDAC; and (iii) target the regulators of CNT3 to restore its (CNT3) expression and assess the effect of its restoration on PDAC progression. We will perform experiments pertaining to molecular biology, immunology, biochemistry and pharmacology utilizing cell-based and animal models of PDAC to accomplish the objectives (Figure 1). The outcomes of this project will generate knowledge on the mechanism of loss of CNT3 in aggressive pancreatic cancer cells and its impact on immunosuppression and PDAC progression. Moreover, the study will suggest proof-of-concept strategies to restore CNT3 expression in metastatic cancer cells for achieving better antitumor immune response, gemcitabine efficacy and suppressing PDAC progression.