Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and new therapies are needed. Cancer-associated fibroblasts (CAFs) can promote PDA progression and are recognized promising therapeutic targets. However, the ongoing characterization of PDA CAF heterogeneity and plasticity and the identification of potential tumor-restraining CAF populations have highlighted the need to further dissect the diverse biology of PDA CAFs to develop effective combination therapies. Using pancreatic organoid/fibroblast co-cultures and organoid-derived transplantation mouse models of PDA, we mechanistically investigated the signaling cascade downstream TGF-beta activation, which is a main driver of myofibroblastic CAF (myCAF) formation. We find that the EGFR/ERBB2 pathway is activated by TGF-beta in a subset of myCAFs, in both murine and human PDA, via amphiregulin induction and autocrine signaling. ERBB activation is important for the maintenance of this myCAF subset, with genetic and pharmacological inhibition of this pathway differentially affecting PDA CAF composition both in culture and mouse models. Importantly, analysis of lung cancer and breast cancer patient samples suggests that our observations in PDA are also relevant to these malignancies. Finally, we reveal a role of this EGFR-activated myCAF subset in promoting local metastatic dissemination in PDA and indicate new potential combination strategies. Our study highlights the need to better dissect PDA CAF heterogeneity also in populations typically considered to be tumor-restraining, in order to develop effective combination strategies for future clinical intervention. Our work also reveals how cancer-targeting therapies can directly affect the surrounding microenvironment with potential clinical implications for various malignancies. Citation Format: Gianluca Mucciolo, Joaquín Araos Henríquez, Sara Pinto Teles, Judhell Manansala, Wenlong Li, Eloise G. Lloyd, Priscilla Cheng, Giulia Biffi. An EGFR-activated subset of myofibroblastic cancer-associated fibroblasts supports local metastatic dissemination in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C039.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified TGF-beta; as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that EGFR/ERBB2 signaling is induced by TGF-beta; in myCAFs through an autocrine process mediated by the ERBB ligand amphiregulin. Inhibition of this ERBB-signaling network in PDAC organoid-derived cultures and mouse models impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, ERBB-activated myCAFs promote local PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest these processes might operate in other malignancies. These data provide functional relevance to CAF heterogeneity and identify a potential target for preventing local tumor invasion in PDAC.

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