EGFR-activated myofibroblasts promote metastasis of pancreatic cancer

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 transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC. [Display omitted] •PDAC malignant cell-secreted TGF-β induces EGFR/ERBB2 activation in myCAFs•EGFR/ERBB2 activation in TGF-β-induced myCAFs is mediated by autocrine amphiregulin•EGFR/ERBB2 inhibition targets a CD90− myCAF subset in PDAC tumors•EGFR-activated myCAFs promote PDAC metastasis Mucciolo et al. demonstrate EGFR/ERBB2 signaling activation in myofibroblastic cancer-associated fibroblasts (myCAFs) in pancreatic ductal adenocarcinoma (PDAC). EGFR-activated myCAFs promote metastasis in PDAC mouse models, revealing a previously unappreciated functional complexity of myCAFs. This knowledge could be used to design therapies that target PDAC malignant cells and tumor-promoting fibroblast populations.