Abstract B102: A model for the origins of transcriptional heterogeneity in human pancreatic ductal adenocarcinoma

Transcriptional heterogeneity in pancreatic ductal adenocarcinoma can be separated into two major phenotypes, commonly referred to as Classical and Basal-like. Substantial work in the field has further refined the phenotypes and highlighted associations with outcome and treatment. However, there remains the fundamental question of how these transcriptional phenotypes originate in the disease. In mice, oncogenic reprogramming by Kras plays a central role in phenotype identity, but how these processes unfold in human tumours is largely unresolved. Based on analysis of the transcriptomes of 490 microdissected patient tumours, 48 single-cell RNA-seq and 10 single-cell multiome profiles, we distilled transcriptional heterogeneity into four high-fidelity phenotypes defined by distinct biological programs. Strikingly, on initial investigation, none of the phenotypes reflected the heterogeneity of the normal pancreas, as is common with cancers of other tissues. Upon investigating temporal emergence, the transcriptional phenotypes were found to arise in two phases from fundamentally different biological processes. Early phenotypes were found to emerge in non-aneuploid cells, and were unexpectedly present in the absence of KRAS mutations in humans. In contrast, late-emerging phenotypes developed after KRAS mutations with the onset of aneuploidy and were decoupled from tumour initiation. Biologically, early phenotypes derived from cell dedifferentiation processes whereas late phenotypes derived from lineage plasticity and epithelial remodelling. Transition from the early to late phenotypes fueled significant tumour heterogeneity and influenced therapeutic responses to KRAS inhibition. Together, these findings help redefine the ontogeny of human pancreatic cancer phenotypes. Citation Format: Sabrina Ge, Paul Tonon, Gun Ho Jang, Yu Zhang, Karen Ng, Eugenia Flores Figueroa, Julie M. Wilson, Anna Dodd, Amy Zhang, Amelia Xu, Michelle Chan-Seng-Yue, Ayah Elqaderi, Ilinca Lungu, Stephanie Ramotar, Shawn Hutchinson, Daniela Bevacqua, Ayelet Borgida, Spring Holter, Pathum Kossinna, Ruth Isserlin, Veronique Voisin, Gary D. Bader, Erica Tsang, Robert C. Grant, Grainne O'Kane, David Tuveson, Oren Parnas, Federico Gaiti, Jennifer J. Knox, Steven Gallinger, Faiyaz Notta. A model for the origins of transcriptional heterogeneity in human pancreatic ductal adenocarcinoma [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 B102.