Deciphering the Role of Stromal Heterogeneity in the Evolution of Aggressive Pancreatic Cancer

Phenotypic heterogeneity within tumors leads to the emergence of aggressive, metastatic, and life-threatening disease. Tumors, however, are comprised of more than just cancer cells, and the complexity of tumor heterogeneity is amplified by contributions from the tumor microenvironment. Non-malignant cells in the tumor stroma, such as fibroblasts, were shown to be reprogrammed by the adjacent cancer cells to support disease progression by multimodal mechanisms. While cancer cell heterogeneity is being slowly unraveled, the heterogeneity of the tumor microenvironment is mostly uncharted. In pancreatic ductal adenocarcinoma (PDAC), which is characterized by an extensive desmoplastic reaction, the characterization of the tumor stroma is exceptionally significant. Our goal is to map the spatial landscape of transcriptional and phenotypic stromal heterogeneity delineating human pancreatic tumors and to identify specific pathways that contribute to the evolution of aggressive pancreatic cancers. We will use Laser capture microdissection (LCM) followed by RNA-sequencing employing both patient samples, as well as patient-derived xenograft (PDX) mouse models. In a preliminary study, we have dissected different stromal regions from a PDAC tumor and were able to differentiate between diverse stromal regions within a single tumor, as well as capture the differences between tumors. In an ongoing study, we are capturing stromal regions from patient samples aiming to define transcriptional heterogeneity of stromal sub-populations. Based on this analysis, we will further investigate genes of interest by performing mechanistic studies and targeted gene deletions in mouse models of pancreatic cancer to pinpoint the subtypes that contribute to the aggressiveness of PDAC. This study will ultimately suggest novel therapeutic approaches, targeting the extensive stroma in PDAC.