YAP1 and TAZ Control Pancreatic Cancer Initiation in Mice by Direct Up-regulation of JAK–STAT3 Signaling

Abstract

Background & AimsPancreatitis is the most important risk factor for pancreatic ductal adenocarcinoma (PDAC). Pancreatitis predisposes to PDAC because it induces a process of acinar cell reprogramming known as acinar-to-ductal metaplasia (ADM)—a precursor of pancreatic intraepithelial neoplasia lesions that can progress to PDAC. Mutations in KRAS are found at the earliest stages of pancreatic tumorigenesis, and it appears to be a gatekeeper to cancer progression. We investigated how mutations in KRAS cooperate with pancreatitis to promote pancreatic cancer progression in mice.MethodsWe generated mice carrying conditional alleles of Yap1 and Taz and disrupted Yap1 and Taz using a Cre-lox recombination strategy in adult mouse pancreatic acinar cells (Yap1fl/fl;Tazfl/fl;Ela1-CreERT2). We crossed these mice with LSL-KrasG12D mice, which express a constitutively active form of KRAS after Cre recombination. Pancreatic tumor initiation and progression were analyzed after chemically induced pancreatitis. We analyzed pancreatic tissues from patients with pancreatitis or PDAC by immunohistochemistry.ResultsOncogenic activation of KRAS in normal, untransformed acinar cells in the pancreatic tissues of mice resulted in increased levels of pancreatitis-induced ADM. Expression of the constitutive active form of KRAS in this system led to activation of the transcriptional regulators YAP1 and TAZ; their function was required for pancreatitis-induced ADM in mice. The JAK–STAT3 pathway was a downstream effector of KRAS signaling via YAP1 and TAZ. YAP1 and TAZ directly mediated transcriptional activation of several genes in the JAK–STAT3 signaling pathway; this could be a mechanism by which acinar cells that express activated KRAS become susceptible to inflammation.ConclusionsWe identified a mechanism by which oncogenic KRAS facilitates ADM and thereby generates the cells that initiate neoplastic progression. This process involves activation of YAP1 and TAZ in acinar cells, which up-regulate JAK–STAT3 signaling to promote development of PDAC in mice.

eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth

“…Here we provide evidence that eIF5A and PEAK1 are major upstream regulators controlling YAP1/TAZ protein levels in PDAC cells. These co-transcriptional activators, in turn, control STFs in the nucleus to regulate cell proliferation and differentiation in normal and malignant cells (2, 17, 19, 21, 27–29, 32, 36–39). Our discovery that eIF5A-PEAK1 couples to YAP1/TAZ signaling provides a plausible mechanism for how PEAK1, a focal adhesion and cytoskeleton-associated kinase, can communicate with the nucleus to control cancer cell proliferation and differentiation.…”

Insulin Receptor and GPCR Crosstalk Stimulates YAP via PI3K and PKD in Pancreatic Cancer Cells

“…Preclinical studies indicated that YAP is a key downstream target of K-Ras signaling required for acinar-to-ductal metaplasia (ADM) and subsequent PanIN progression into PDAC (40, 41). Furthermore, amplification and overexpression of Yap can substitute for mutant K-Ras expression in PDAC (26).…”

A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy

“…In addition, YAP1 acts as a critical transcriptional switch downstream of the KRAS‐MAPK pathway and amplifies the expression of genes encoding secretory factors to promote neoplastic proliferation and tumorigenic stromal response in the TME . In a recent study, pancreatic tumor initiation was studied in Yap1 / Taz disrupted KRas mutant mice . In this study, Yap1 and Taz directly and independently upregulate transcriptional activation of several genes in the Jak‐Stat3 signaling pathway, which induces acinar‐to‐ductal metaplasia, a precursor of pancreatic ductal adenocarcinoma.…”