Abstract 3646: Distinct functions of pancreatic stellate cells in PDAC stromal evolution

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in the United States with a five-year relative survival rate of 10.8%. After surgery, radiation and chemotherapy are the next lines of therapy. However, these treatments have not significantly improved clinical outcomes due in part to its unique and characteristic desmoplasia, which limits treatment efficacy. Cancer-associated fibroblasts (CAFs) have been shown to contribute in PDAC’s stromal reaction in part viasecretion of extracellular matrix (ECM) components and growth factors, suggesting that CAFs are pro-tumorigenic. This understanding led to several CAF ablation preclinical studies; surprisingly, these studies demonstrated tumor-suppressive potential for CAFs, highlighting the functional heterogeneity among CAFs in PDAC. This emphasizes the need for greater developmental understanding of this influential cell population. Lineage tracing via our recently established Fabp4-Cre;Rosa26mTmG mouse model revealed that pancreatic stellate cells (PSCs), thought to be the main cellular origin of PDAC CAFs, contribute to a minor faction of CAFs yet appear to have non-redundant functions to alternatively-derived CAFs. Here we delve further into the specific functions of PSC-derived CAFs via single-cell RNA sequencing of pancreatic stellate cells in healthy and tumor pancreas with our Fabp4-Cre;Rosa26mTmG mouse model. To our surprise, initial scRNA-seq analysis illustrated that quiescent pancreatic stellate cells from healthy tissue appear to be more heterogeneous to PSC-derived CAFs, with quiescent pancreatic stellate cells clustering into three “super clusters” while PSC-derived CAFs clusters into one “super cluster”. Additionally, clusters specific to normal pancreas tissue revealed potential transcripts-of-interest that are anti-tumorigenic. Current efforts seek to analyze stromal evolution with respect to CAF cell of origin in pre-malignant lesions and throughout stepwise tumorigenesis to metastasis. Furthermore, we are investigating the functional significance of potentially anti-tumorigenic factors lost from the PSC compartment upon differentiation to a CAF phenotype during PDAC progression. These findings shed light on the increasingly appreciated heterogeneity of PDAC CAFs, whilst suggesting that PSC-derived CAFs may be specifically targeted as a singular cell population for therapeutic treatment. Importantly, these findings help gain a greater understanding of PDAC disease progression and development in order to better serve patient care. Citation Format: M. Kathrina Casapao Onate, Matthew Schleisman, Zheng Xia, Mara H. Sherman. Distinct functions of pancreatic stellate cells in PDAC stromal evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3646.