EGFR-activated myofibroblasts promote metastasis of pancreatic cancer

• DOI: 10.1016/j.ccell.2023.12.002
• Publication Date: 2023-12-28T15:27:05Z
• Authors: Gianluca Mucciolo; Joaquín Araos Hen...; Muntadher Jihad; Sara Pinto Teles; Judhell S. Manansala; Wenlong Li; Sally Ashworth; Eloise G. Lloyd; Priscilla S.W. Cheng; Weike Luo; Akanksha Anand; Ashley Sawle; Anna Piskorz; Giulia Biffi
• Keywords: myCAFs; EGFR/ERBB2 signaling; pancreatic cancer; Amphiregulin; TGF-β signaling; Pancreatic Neoplasms; Mice; Amphiregulin; EGFR/ERBB2 signaling; TGF-β signaling; cancer-associated fibroblasts; metastasis; myCAFs; pancreatic cancer; tumor microenvironment; Transforming Growth Factor beta; Tumor Microenvironment; metastasis; tumor microenvironment; Animals; Myofibroblasts; cancer-associated fibroblasts; Carcinoma, Pancreatic Ductal; Signal Transduction

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 limited the development effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as main driver myofibroblastic CAFs (myCAFs). Here, we show that epidermal receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated amphiregulin. Inhibition this EGFR/ERBB2-signaling network PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated promote metastasis mice, unmasking functional significance myCAF Finally, analyses other cancer datasets suggest processes might operate malignancies. These data provide relevance to heterogeneity identify candidate target for preventing tumor invasion PDAC.