Abstract I01: Mechanisms and consequences of pancreatic cancer stromal evolution

Abstract

Abstract The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of a fibroinflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type driving the stromal reaction in PDAC. Recent reports suggest that PDAC CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types that support and others that suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas that can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of CAFs in the PDAC microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have taken advantage of a novel mouse model we developed to track PSC differentiation and function during pancreatic tumor progression in vivo. This model leverages the unique lipid-storing origin of PSC-derived CAFs, and enables their distinction from CAFs of non-PSC origin for the first time. We hypothesized that PSC-derived fibroblasts in the PDAC microenvironment are a proinflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. Using our model, we have interrogated PDAC stromal heterogeneity and functional significance, analyzed the distinguishing features of CAF subpopulations from disparate origins, and determined the significance of genetic alterations in the epithelial compartment on stromal cell fate and function. Together, these studies have the potential to lay the foundation for development of stroma-targeted therapies based on careful lineage tracing and molecular data. These findings shed light on mechanisms of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors. Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [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 I01.