Loss of Wasl improves pancreatic cancer outcome.

Ana Hidalgo-Sastre,Jens T Siveke,Maximilian Reichert,Ali Sameer Abdulghani Altaee,Zahra Dantes,Judit Desztics,Guido Von Figura,Henrik Einwächter,Marina Lesina,Roland Rad,Blessing Bassey-Archibong,Rupert Öllinger,Roland M Schmid,Juliet M Daniel,Thomas Engleiter,Hilal Kabadayi Ensarioglu,Katharina Schulte,K Steiger ,Lyndsay G A Rayner ,Clara Lubeseder‐Martellato

doi:10.1172/jci.insight.127275

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.

Highlights

Activating mutations of the Kras oncogene are the driver mutations for pancreatic ductal adenocarcinomas (PDACs), which is one of, if not the, most lethal human cancer with a 5-year survival rate under 5% [1]
We show a displacement of the N-WASP binding partners WASP-interacting protein (WIP) and p120ctn upon deletion of Wasl, which resulted in increased endocytosis — linked to accumulation of the components of the β-catenin destruction complex YAP1 and dephosphorylated, inactive β-catenin in tumor cells
In line with the increased amount of active β-catenin expression observed in CK-NΔPanc pancreatic tissues, our RNA sequencing (RNAseq) data reveal increased expression of several β-catenin gene targets (Supplemental Table 3), which were validated by reverse transcription PCR (RT-PCR) (Supplemental Figure 1G)

Summary

Introduction

Activating mutations of the Kras oncogene are the driver mutations for pancreatic ductal adenocarcinomas (PDACs), which is one of, if not the, most lethal human cancer with a 5-year survival rate under 5% [1]. Several studies suggest that PDAC develops through preneoplastic lesions originating from acinar-to-ductal metaplasia (ADM) [3,4,5]. We further showed that this ADM is dependent on the neural Wiskott-Aldrich syndrome protein (N-WASP, encoded by the Wasl gene). Actin polymerization has been shown to be crucial for PDAC development, and both CDC42 and PIP2 are effectors of KRAS [14,15,16]. N-WASP may function as a driver for PDAC development and progression.

Methods

Results

Conclusion