Integrin alpha 1 (ITGA1) and cellular stress in pancreatic ductal adenocarcinoma (PDAC)

Pancreatic cancer's highly invasive characteristics, lack of biomarkers, and limited therapeutic targets lead to a poor 5-year survival rate of 7%. Integrin alpha one (ITGA1) is a cell surface receptor for collagen and laminin that activates downstream signaling cascades that are important in cancer progression. The proteomic profile of ITGA1-depleted pancreatic cancer cells identified elevated levels of calcium ATPases (SERCA1/3), which are regulators of ER calcium homeostasis and the unfolded-protein response (UPR). Downstream signaling of UPR can activate survival mechanisms to confer stress-resistant states in cancer cells. The central hypothesis of this project is that ITGA1 is required for resistance against cellular stress in pancreatic cancer. We aim to investigate ITGA1's role in cell survival in response to stress induced by dysregulation of ER calcium homeostasis and extracellular metabolites (i.e. glutamine, glucose, sodium pyruvate) that are commonly found to be altered in the pancreatic tumor microenvironment. Our results indicate that ITGA1's role in regulating stress responses is cell line specific. PANC1 cell viability was not significantly affected by ER stress but induces a morphology shift to favor an ITGA1-dependent mesenchymal morphology. Surprisingly, FG cells were highly sensitive to ER stress in an ITGA1-independent manner. Due to the drastic differences between PANC1 and FG cell responses to ER stress, we opted to pharmacologically target proteins that were specific to PANC1 cells. In this regard, we've identified that PANC1 cells are particularly sensitive to dual ITGA1/PARP inhibition - a promising therapeutic strategy to further sensitize a subset of PDAC cells to chemotherapy treatment. Lastly, our study confirms that L-glutamine is an important source of carbon for some PDAC cells. Specifically, FG cells require ITGA1 for L-glutamine mediated cell growth on collagen substrates, an effect that is not prominent in the absence of collagen or in the ITGA1-dependent ER stress resistant PANC1 cells.