Abstract 1395: Unraveling the interplay between tumor heterogeneity and microenvironment in pancreatic ductal adenocarcinoma evolution and its clinical implications

Abstract

Abstract Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. We performed single-cell RNA sequencing of primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. We discovered that even a small proportion (~30%) of basal-like ductal cells in primary PDAC was associated with poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression. Diverse immune cell populations, including naive SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells. The proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. Overall, our study provides a valuable resource for better understanding the roles of ITH and TME in PDAC evolution and their clinical relevance in the treatment of PDAC. Citation Format: Hyemin Kim, Hyong-oh Jeong, Se-Hoon Lee, Kwang Hyuck Lee, Kyu Taek Lee, Jong Kyun Lee, Min Woo Lee, Semin Lee, Joo Kyung Park. Unraveling the interplay between tumor heterogeneity and microenvironment in pancreatic ductal adenocarcinoma evolution and its clinical implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1395.