Yes-Associated Protein 1 Plays Major Roles in Pancreatic Stellate Cell Activation and Fibroinflammatory Responses

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.

Lipoxin Alleviates Diabetic Vascular Calcification via the YAP Pathway

“…In addition, western blot results showed that the diabetic aorta treated with LX exhibited less COL1, which accounted for 65% of the total collagen in the normal vessel [90] (Figure 4F). In vitro [92]. This is in line with literature showing that YAP signalling plays a role in extracellular matrix remodelling, especially in regulating collagen production [92].…”

“…In vitro [92]. This is in line with literature showing that YAP signalling plays a role in extracellular matrix remodelling, especially in regulating collagen production [92].…”

Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas

“…Interestingly, the plasma sEV-associated proteins ( Figure 3B,C) identified in plasma with AUC ≥ 0.7 case:control classifier performance in both the LUAD and PDAC cohorts denote a pan-adenocarcinoma sEV signature and suggest intriguing implications regarding markers that yield insight into cancer-host interchange within the tumor microenvironment. For example, PDGF (Platelet-derived growth factor subunit A) has been shown to be involved in recruitment and activation of cancer-associated fibroblasts in lung adenocarcinoma [31] and to also exert similar effect on pancreatic stellate cells and fibroblasts in PDAC tumors [32,33]. Tumor derived VEGFC (Vascular endothelial growth factor C) has been demonstrated to support metastatic expansion of primary tumors into the lymphatic vasculature in many tumor types, challenging the traditional concept of a purely passive role of the lymphatic vessels in cancer metastasis [34][35][36].…”

Pancreatic stellate cells: the top managers of the pancreatic tumor microenvironment.

“…Several factors of the MAPK pathway, such as p38, reduce YAP levels in the PSC. YAP knockdown inhibits the activation of Akt and ERK and also suppresses the expression of fibrous and inflammatory proteins both with and cytes [54]. Quiescent PSCs have receptors for cholecystokinin, and upon binding, they react with the release of acetylcholine, which in turn acts on cells of the pancreatic acinus [55].…”