Author:
Mucciolo Gianluca,Henríquez Joaquín Araos,Teles Sara Pinto,Manansala Judhell S.,Jihad Muntadher,Li Wenlong,Lloyd Eloise G.,Cheng Priscilla S.W.,Biffi Giulia
Abstract
SUMMARYPancreatic 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-β as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that EGFR/ERBB2 signaling is induced by TGF-β 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.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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