Loss of Wasl improves pancreatic cancer outcome

• DOI: 10.1172/jci.insight.127275
• Publication Date: 2020-05-20T15:01:32Z
• Authors: Ana Hidalgo-Sastre; Judit Desztics; Zahra Dantes; Katharina Schulte; Hilal Kabadayi En...; Blessing Bassey-A...; Rupert Öllinger; Thomas Engleiter; Lyndsay Rayner; Henrik Einwächter; Juliet M. Daniel; Ali Sameer Abdulg...; Katia Steiger; Marina Lesina; Roland Rad; Maximilian Reichert; Guido von Figura; Jens T. Siveke; Roland M. Schmid; Clara Lubeseder-M...
• Keywords: 0301 basic medicine; Carcinogenesis; Medizin; Wiskott-Aldrich Syndrome Protein, Neuronal; Mice, Transgenic; YAP1; Cancer research; Gene; Mice; 03 medical and health sciences; Role of Hippo Signaling Pathway in Mechanotransduction; Biochemistry, Genetics and Molecular Biology; Health Sciences; KRAS; Genetics; Animals; Humans; Molecular Biology; Biology; Cancer; Life Sciences; The p53 Signaling Network in Cancer Research; Neoplasms, Experimental; Cell Biology; Pancreatic cancer; Fibroblast Growth Factor Signaling Pathway; Tumor progression; Colorectal cancer; Downregulation and upregulation; Loss function; ddc:; 3. Good health; Pancreatic Neoplasms; Phenotype; Oncology; FOS: Biological sciences; Medicine; Tumor Suppressor Protein p53; Transcription factor; Phenocopy

Several studies have suggested an oncogenic role for the neural Wiskott-Aldrich syndrome protein (N-WASP, encoded by Wasl gene), but thus far, little is known about its function in pancreatic ductal adenocarcinoma (PDAC). In this study, we performed silico analysis of WASL expression PDAC patients and found a correlation between low prolonged survival. To clarify carcinogenesis, used 2 Kras-based mouse models with pancreas-specific deletion. line human data, both had increased survival benefit due to either impaired tumor development presence suppressor Trp53 or delayed progression senescent phenotype upon genetic ablation Trp53. Mechanistically, loss resulted cell-autonomous senescence through displacement N-WASP binding partners WASP-interacting (WIP) p120ctn; vesicular accumulation GSK3β, as well YAP1 phosphorylated β-catenin, which are components destruction complex; upregulation Cdkn1a(p21), master regulator senescence. Our findings, thus, indicate that functions manner promoting deregulation p120-catenin/β-catenin/p21 pathway. Therefore, strategies reduce activity might improve outcomes patients.