Pancreatic Cancer-Associated Fibroblasts: Function, Detection, and Regulation

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PROJECT SUMMARY/ABSTRACT Pancreatic Cancer (PC) survival rates are very low and even lower for patients from low socioeconomic backgrounds/circumstances (SES), often living in geographic locations with limited access to care. One explanation for this disparity could be chronic stress. Several researchers, including our Collaborative Investigator, have shown that Black individuals and those living in neighborhoods with low SES endure sustained exposure to stressful circumstances (e.g. systemic racism, lack of resources), which impact mental health (e.g. anxiety, fear) and augment PC. Neighborhood SES (nSES) hence serve as a macro-environmental indicator of chronic stress, independent of a patient’s SES and mental health. Low nSES, can for example prevent cancer cell death and promote its aggressiveness. If the biologic basis of PC health disparities is to be elucidated, studies proposing to understand how, for example, nSES impacts PC are needed. The parent grant focuses on studying the non-cancerous cells and natural scaffold units of the pancreas in PC. Of note, the specific molecules studied are implicated in chronic stress. In fact, some chronic stress features, such as glutamate excess, are simulated by the non-cancerous units of the pancreas during PC. We reported that pro-tumorigenic activation of these units are indicative of unfavorable PC patient outcomes. Interestingly the same units also are implicated in synapse stability in brain and in the generation of small membranous vesicles that are produced by these units and can be detected in blood. Building on this, our parent grant proposes to: i) reveal how the natural scaffold of these units regulates pro tumoral unit functions; ii) assess whether detection of the unique unit-generated membranous vesicles inform on the pancreatic tumor-promoting vs. tumor-suppressing, status of PC patient’s organ; and iii) question if the molecules relevant for driving pro-tumoral function of the units can be targeted. Here we plan to expand this scope by forging a multidisciplinary partnership with a disparity research expert Dr. Shannon Lynch in the form of 3 specific new aims: Aim 1: Measure biomarkers (high Glu, & others) and macro-environmental measures of chronic stress (nSES; racial segregation) to determine if high levels of environmental stress correlate with biologic stress. Aim 2: Evaluate the correlation between chronic stress measures (biomarkers, macro-environmental measures) and pro-tumoral circulating biomarkers in vesicles informing on local stress-like microenvironments. Aim 3: Determine if microenvironment-indicative biomarkers are associated with PC patient survival time, alone and after adjustment for comprehensive chronic stress measures and race/ethnicity in multivariable regression models.