Skip to Content
Merck

Loss of Wasl improves pancreatic cancer outcome.

JCI insight (2020-05-22)
Ana Hidalgo-Sastre, Judit Desztics, Zahra Dantes, Katharina Schulte, Hilal Kabadayi Ensarioglu, Blessing Bassey-Archibong, Rupert Öllinger, Thomas Engleiter, Lyndsay Rayner, Henrik Einwächter, Juliet M Daniel, Ali Sameer Abdulghani Altaee, Katia Steiger, Marina Lesina, Roland Rad, Maximilian Reichert, Guido von Figura, Jens T Siveke, Roland M Schmid, Clara Lubeseder-Martellato
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
StableCell DMEM - high glucose, With 4500 mg/L glucose, stable glutamine, and sodium bicarbonate, without sodium pyruvate., liquid, sterile-filtered, suitable for cell culture
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Salinomycin, Ready Made Solution, from Streptomyces albus, ≥98% (HPLC)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
5-(N-Ethyl-N-isopropyl)amiloride
SKU
Pack Size
Availability
Price
Quantity