Abstract IA-03: Functional heterogeneity of fibroblast populations in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is especially lethal among cancers because current treatments are few and ineffective. One key stromal factor thought to contribute to the dismal prognosis of PDAC is the presence of cancer-associated fibroblasts (CAFs). However, CAF-targeting therapeutic strategies have so far failed. Recently, providing an explanation for this apparent contrasting observations, phenotypically distinct PDAC CAF subtypes have been discovered. We previously described two main PDAC CAF populations that are defined by distinct targetable molecular mechanisms: TGF-beta-dependent myofibroblastic CAFs (myCAFs) and IL-1-dependent inflammatory CAFs (iCAFs) (J Exp Med 2017). We also demonstrated how the activation of one pathway (i.e., TGF-beta signaling) blocks the activation of another (i.e., IL-1 signaling), leading to this CAF heterogeneity (Cancer Discovery 2019). Despite our progress, the roles of distinct PDAC CAF subtypes remain to be largely elucidated. Indeed, the ability of myCAFs and iCAFs to at least partially interconvert and the lack of genetically engineered mouse models (GEMMs) for their in vivo manipulation have so far hindered careful investigation of their functions in PDAC progression. To overcome these challenges, we have engineered new mouse models and ‘CAF-locked’ fibroblast lines that enable to alter CAF composition in vitro and in vivo. Leveraging these new models, we are starting to understand the respective crosstalk of iCAFs and myCAFs with each other, with PDAC malignant cells, with immune cells and with other stromal cells. Improving PDAC survival for all patients will likely require a better understanding of the complex nature of the tumor microenvironment in these heterogeneous cancers. While further genetic manipulation of myCAF (e.g., EGFR-activated myCAFs – Cancer Cell 2024) and iCAF subsets will be required to achieve that, our studies are crucial to begin to decipher this complexity. Citation Format: Giulia Biffi. Functional heterogeneity of fibroblast populations in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr IA-03.