Abstract I07: Multimodal evolutionary dynamics of pancreatic cancer

Abstract

Abstract The pancreatic cancer genome has been well annotated through multiple large-scale efforts. However, the extent to which specific genes correspond to specific subtypes of PDA or to specific patterns of failure remains a work in progress. Transcriptional subtypes of PDA have also emerged as an important variable for this disease, with classical-type and basal-like profiles now recognized as potential extremes of a range of phenotypes. We integrated evolutionary analysis and expression profiling in multiregion sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq defined basal-like subtype. In patients with coexisting basal/squamous and classical/glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical/glandular tumor. Cancers with squamous features were notable for MYC amplification. We also identify entosis, a unique form of cell competition in which one cancer cell engulfs another, as a predominant feature of squamous morphology in PDAC. Entosis is associated with profound intercellular heterogeneity for MYC copy number, suggesting a mechanistic link between MYC amplification, cell competition and the microenvironment in squamous features. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology, and genomic alterations in the context of clonal evolution of pancreatic cancer. Citation Format: Christine Iacobuzio-Donahue. Multimodal evolutionary dynamics of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I07.