Abstract
Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates cell differentiation and morphology in many cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer cells and pancreatic stellate cells (PaSC) in the stroma.Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-KrasG12D/+ (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFβ1)-stimulated PaSC.Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFβ1, and PDGF pathways regulates PaSC activity and growth.
Highlights
Acute (AP), recurrent acute (RAP), and chronic pancreatitis Chronic pancreatitis (CP) are inflammatory disorders of the exocrine pancreas associated with significant morbidity, a high rate of hospitalizations and mortality (Peery et al, 2012; Lew et al, 2017)
Previous studies indicate that effectors of the Hippo signaling system including TEAD1 and its transcriptional activator Yes-associated protein 1 (YAP) are integral components of the embryonic development of human pancreas (Cebola et al, 2015) and its expression is recapitulated during progression of pancreatic disorders (Kapoor et al, 2014; Zhang et al, 2014; Morvaridi et al, 2015; Hao et al, 2017)
Histological analysis of pancreatic tissues from pancreatic ductal adenocarcinoma (PDAC) patients and murine models of pancreatic cancer shows that YAP is upregulated in precancerous lesions (Pancreatic Intraepithelial Neoplasia, PanIN) and cancer cells as well as in activated pancreatic stellate cells (PaSC) in the stroma (Kapoor et al, 2014; Zhang et al, 2014; Morvaridi et al, 2015; Hao et al, 2017)
Summary
Acute (AP), recurrent acute (RAP), and chronic pancreatitis CP are inflammatory disorders of the exocrine pancreas associated with significant morbidity, a high rate of hospitalizations and mortality (Peery et al, 2012; Lew et al, 2017). CP of diverse etiologies significantly increases the risk for pancreatic ductal adenocarcinoma (PDAC) (Lew et al, 2017; Yang and Forsmark, 2017). In this respect, epidemiological studies indicate that CP patients at 5 years after diagnosis have a nearly eightfold increased risk of acquiring PDAC (Kirkegard et al, 2017). Accumulating evidence supports the concept that pancreatitis is initiated in the pancreatic acinar cell, the main cell type in the exocrine parenchyma, with stresses causing cellular dysfunction that triggers activation of pro-inflammatory signaling, activation of neighboring quiescent pancreatic stellate cells (PaSC), and immune cell infiltration into the pancreas (Gukovskaya et al, 2019). Recent studies showed that YAP is expressed in pancreas tissues in pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer cells and pancreatic stellate cells (PaSC) in the stroma
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