Abstract A031: Interrogating microenvironmental changes that impact early pancreatic cancer development

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with one of the lowest five-year survival rates of all cancers. Low grade, premalignant pancreatic intraepithelial neoplasias (PanINs) are common in the general population, but despite expression of mutant KRAS, the vast majority of these lesions will never progress to cancer. Understanding how additional genetic or epigenetic changes as well as changes to the tumor microenvironment contribute to PanIN to PDAC progression is critical and has the potential to reveal mechanisms of interception for this deadly disease. Our previous work identified the prolyl isomerase PIN1 as a critical factor in the tumor microenvironment for growth of a subset of pancreatic cancer cell lines. Loss of PIN1 in the tumor microenvironment restricted in vivo growth of multiple KPC cell lines. We identified distinct fibroblast phenotypes in the absence of microenvironmental PIN1 expression or function. These changes in fibroblast state drive significant changes in the extracellular matrix and growth factor expression, both of which impact the crosstalk to and behavior of the neoplastic cells. We are continuing to use conditional PIN1 knockout mice to interrogate the specific cell types responsible for the observed tumor-restrictive phenotype and are using single cell sequencing to better understand how changes to individual cell types affect multiple cell populations to inhibit tumor growth. In addition, we are comparing the fibroblast phenotypes observed in our mouse models to those found in tumor-promoting versus tumor-restrictive microenvironments in human tissues. These tissues include autopsy pancreata with low grade PanIN lesions as well as PDAC resection specimens with low and high grade PanINs. We are creating organoid and cell line models of epithelial and stromal cells from normal human pancreata to support complex co-culture engineered models of early disease progression. By integrating across mouse and human model systems, we strive to understand the crosstalk that permits progression of pancreatic cancer and to identify targets to intercept this process. Citation Format: Tana Gazdik, Madeline Kuhn, Chloe Bowman, Eric Carlson, Kyra Lindley, Ellen M. Langer. Interrogating microenvironmental changes that impact early pancreatic cancer development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A031.