UC San Diego

Pancreatic cancer is notoriously known for being aggressive and resistant to chemotherapy. It has one of the highest rates of recurrence among all cancers and a poor survival rate even after treatment. The tumor microenvironment in pancreatic cancer, also known as a “niche”, is characterized by the deposition of a dense extracellular matrix (ECM). To establish a tumor at a primary or metastatic site, tumor-initiating cells (TICs) must adapt and survive in a highly hostile environment characterized by hypoxia, nutrient deprivation, and oxidative stress, together known as isolation stress. TICs accomplish this by gaining stem-like features which ultimately lead to a stress-tolerant phenotype. Pancreatic cancer cells upregulate a receptor called lysophosphatidic acid receptor-4 (LPAR4) in response to isolation stress. LPAR4 expression is necessary and sufficient to establish a tumor-initiating niche, which plays an important role in cancer progression. A characteristic of this niche is the enrichment of the ECM component fibronectin (FN), which interacts with cells through cell-surface integrin receptors. These interactions activate various signaling molecules such as the transcriptional regulator Yes-associated protein (YAP), consequently driving cancer stemness. In this study, I investigate the adaptive gain of a stress-tolerant phenotype in LPAR4- cells mediated by a FN-enriched ECM deposited by LPAR4+ cells. I report that the ectopic expression of LPAR4 in pancreatic cancer cells is sufficient to induce a stress-tolerant phenotype and YAP activation, through the elevated expression of FN. Knockout of FN in LPAR4+ cells can hamper YAP activation, emphasizing the crucial role of FN in YAP signaling. Furthermore, the ECM deposited by LPAR4+ cells is sufficient to confer the stress-tolerant phenotype to neighboring LPAR4- cells through paracrine signaling by a fibronectin-dependent pathway, leading to integrin-mediated activation of YAP and expression of YAP targets CTGF and CYR61. A pure FN-matrix is sufficient to induce YAP activation in LPAR4- cells, indicating that FN is the key ECM component that interacts with cell surface integrin receptors to drive cancer stemness in response to isolation stress. Together, all these factors help tumor-initiating cells to survive isolation stress, resist chemotherapy, and form aggressive tumors, leading to pancreatic cancer progression.