Loss of Wasl improves pancreatic cancer outcome
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Date
2020
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Abstract
Several studies have suggested an oncogenic role for the neural Wiskott-Aldrich syndrome protein (N-WASP, encoded by the Wasl gene), but thus far, little is known about its function in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed in silico analysis of WASL expression in PDAC patients and found a correlation between low WASL expression and prolonged survival. To clarify the role of Wasl in pancreatic carcinogenesis, we used 2 oncogenic Kras-based PDAC mouse models with pancreas-specific Wasl deletion. In line with human data, both mouse models had an increased survival benefit due to either impaired tumor development in the presence of the tumor suppressor Trp53 or the delayed tumor progression and senescent phenotype upon genetic ablation of Trp53. Mechanistically, loss of Wasl resulted in cell-autonomous senescence through displacement of the N-WASP binding partners WASP-interacting protein (WIP) and p120ctn; vesicular accumulation of GSK3β, as well as YAP1 and phosphorylated β-catenin, which are components of the destruction complex; and upregulation of Cdkn1a(p21), a master regulator of senescence. Our findings, thus, indicate that Wasl functions in an oncogenic manner in PDAC by promoting the deregulation of the p120-catenin/β-catenin/p21 pathway. Therefore, strategies to reduce N-WASP activity might improve the survival outcomes of PDAC patients. © 2020, American Society for Clinical Investigation.
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Animals , Humans , Mice , Mice, Transgenic , Neoplasms, Experimental , Pancreatic Neoplasms , Tumor Suppressor Protein p53 , Wiskott-Aldrich Syndrome Protein, Neuronal , beta catenin , beta galactosidase , binding protein , cyclin D1 , cyclin dependent kinase inhibitor 1A , gamma interferon , glycogen synthase kinase 3beta , immunoglobulin enhancer binding protein , interleukin 6 , Ki 67 antigen , neural Wiskott Aldrich syndrome protein , protein p120 , protein p21 , STAT3 protein , transcription factor , transcription factor KAISO , transcription factor Yap1 , unclassified drug , WASP interacting protein , neural Wiskott Aldrich syndrome protein , protein p53 , TP53 protein, human , Trp53 protein, mouse , WASL protein, human , Wasl protein, mouse , animal cell , animal experiment , animal model , animal tissue , Article , bioaccumulation , cancer growth , cancer survival , carcinogenesis , cell aging , cellular distribution , computer model , controlled study , deregulation , endocytosis , enzyme activity , enzyme inhibition , enzyme regulation , gene activity , gene deletion , gene expression , gene frequency , gene function , gene loss , genotype , human , human tissue , loss of function mutation , mouse , nonhuman , oncogene K ras , pancreas adenocarcinoma , pancreatic cancer cell line , phenotype , protein dephosphorylation , protein expression , protein induction , protein interaction , protein localization , protein phosphorylation , protein stability , risk benefit analysis , RNA sequencing , signal transduction , survival time , tumor promotion , tumor suppressor gene , upregulation , WASL gene , animal , experimental neoplasm , genetics , metabolism , pancreas tumor , pathology , transgenic mouse