Abstract A108: Spatial transcriptomic analysis of venous invasion in human pancreatic adenocarcinoma reveals widespread attenuation in features associated with aggression and mortality

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Abstract In pancreatic ductal adenocarcinoma (PDAC), venous invasion (VI) is a necessary precursor to hematogenous dissemination, but little is known about the molecular features of VI. To investigate these features, we performed spatial transcriptomic analysis of foci of VI, PDAC in stroma (PDAC-S), and normal pancreatic duct in surgically resected human PDAC tissue samples from eight treatment naïve patients. We performed GeoMx Digital Spatial Profiler analysis of 35 regions of VI, 39 regions of PDAC-S, and 14 regions of normal duct. Through unbiased hierarchical clustering, we observe that normal duct foci cluster more closely to VI than to PDAC-S. When comparing differentially expressed genes (DEGs) between VI and PDAC-S, we observe that VI shows high expression of genes which are highly expressed by normal duct relative to PDAC-S. These genes have well characterized roles in normal pancreatic exocrine function and development. Within the upregulated VI DEGs, we observe another group of genes which are elevated in VI relative to both PDAC-S and normal duct, which includes mucins, cell adhesion molecules such as CEACAM5 and TSPAN8, and transcription factors such as FOS and ZFPM1. Pathway analysis of the differentially expressed genes reveals enrichment for MYC signaling and oxidative phosphorylation. When compared to PDAC-S, VI demonstrates downregulation of many genes involved in epithelial-mesenchymal-transition (EMT), such as collagens, laminins, S100 proteins and other EMT-associated genes such as FN1, VIM, MMP11, TGFBI, TGM2, and POSTN. When compared to PDAC-S, VI shows increased expression of genes from the classical phenotype of the Moffitt classification, while PDAC-S has increased expression of the basal-like signature. We performed morphologic subtyping of the VI foci, with 11 samples classified as VI-Destructive (disruption of the venous lumen and associated fibrosis) and 22 samples classified as VI intraepithelial neoplasia-like or VI-IN-Like (complete circumferential replacement of the venous lumen). Compared to VI-IN-Like, VI-Destructive shows increased expression of EMT-associated genes, increased expression of the basal-like gene signature, and reduced expression of the classical signature. Compared to VI-IN-Like and PDAC-S, VI-Destructive showed intermediate expression of EMT-associated genes. Transfer learning of our data to publicly available RNA-Seq data sets reveals that metastatic pancreatic cancer bears greater similarity to PDAC-S than to VI, and circulating tumor cells express features of both VI and PDAC-S. Overall, our data suggest that VI regains transcriptional features of normal ductal epithelium, and demonstrates widespread downregulation of features associated with aggression and mortality, such as genes associated with EMT and the basal-like phenotype. We observe that this transcriptional shift is associated predominantly with the VI-IN-Like morphology, and that VI-Destructive is a transcriptional intermediate between VI-IN-Like and PDAC-S. Citation Format: Alexander T.F. Bell, Peter Chianchiano, Katsuya Hirose, Doreen Gisder, Alexander I. Damanakis, Luciane T. Kagohara, Elana J. Fertig, Laura D. Wood. Spatial transcriptomic analysis of venous invasion in human pancreatic adenocarcinoma reveals widespread attenuation in features associated with aggression and mortality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A108.