Abstract 150: Stromal cell plasticity and immune surveillance revealed by single-cell transcriptomics

Abstract

Abstract Pancreatic ductal adenocarcinomas are typically characterized by a highly desmoplastic stroma, which is dense in collagen and other extracellular matrix components that limit access to the growing tumor by immune cells and targeted therapies. ECM components are mainly deposited by cancer-associated fibroblasts (CAFs), which are thought to arise primarily from pancreatic stellate cells and have been shown to polarize into at least two distinct subtypes within the tumor microenvironment in response to extracellular ligands. Recent studies have suggested potentially antagonistic roles for the different CAF subtypes in either promoting or restraining tumor growth. While depletion of the restrictive desmoplasia is likely to be a desirable therapeutic avenue, a complete understanding of phenotypic variation and interconversion between CAF populations will be essential for designing targeted therapies. Using single-cell RNAseq, we have profiled the non-immune stromal cells of pancreatic ductal adenocarcinomas in the KPC mouse model, as well as from orthotopically transplanted organoid-derived pancreatic tumors. In addition to the canonically reported myofibroblastic and inflammatory CAF subtypes, we observe at least one additional distinct type-I collagen expressing fibroblastic cell type in the tumor microenvironment. The high degree of transcriptional divergence suggests that these CAFs may arise from distinct progenitors, whereas myo- and inflammatory-CAFs lie along a continuous pseudotemporal gradient marked by signatures of transcriptional programs driven by extracellular ligand signaling, including Wnt-family genes. Our single-cell transcriptomic results point toward pathway utilization that could be exploited for modulating PDAC desmoplasia and enabling targeted combination therapies. Citation Format: Claire Regan, Yuan Hao, Jonathan Preall. Stromal cell plasticity and immune surveillance revealed by single-cell transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 150.