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Loss of Wasl improves pancreatic cancer outcome
Ana Hidalgo-Sastre, … , Roland M. Schmid, Clara Lubeseder-Martellato
Ana Hidalgo-Sastre, … , Roland M. Schmid, Clara Lubeseder-Martellato
Published May 21, 2020
Citation Information: JCI Insight. 2020;5(10):e127275. https://doi.org/10.1172/jci.insight.127275.
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Research Article Oncology

Loss of Wasl improves pancreatic cancer outcome

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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.

Authors

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

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Figure 1

Low WASL correlates with improved survival, and loss of Wasl in oncogenic Kras–driven mouse model for PDAC impairs tumor development.

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Low WASL correlates with improved survival, and loss of Wasl in oncogeni...
(A) Kaplan-Meier survival curve of PDAC patients stratified for WASL expression using the UCSC Xena genomic browser. (B) Representative H&E staining of pancreata of 4-week-old mice. (C) H&E stainings; arrowheads highlight mast cells. Scale bars: 50 μM. (D) Morphometric quantification of the amount of ADM lesions, exocrine pancreas, and fat within the pancreatic tissue in 4-week-old animals. CK (n = 7) and CK-NΔPanc (n = 3). Data represent mean ± SEM. Student′s t test. (E) RNAseq was performed from 4 mice per group. The bar graph from the top upregulated and downregulated pathways (combined score: P value multiplied by z score) in 4-week-old CKNΔPanc mice. The pathways were obtained after running the differentially regulated genes (n = 155) listed in Supplemental Table 1 through the gene set enrichment program Enrichr. (F) Enrichment plots generated by the GSEA tool showing the signatures that were enriched in the CK-NΔPanc pancreata. (G) Kaplan-Meier tumor-free curves for CK (n = 12), CK-Nhet (n = 12), and CK-NΔPanc (n = 12) mice. (H) Upper panels show macroscopic pictures of organs of endpoint mice. Note the tiny pancreas in the CKP-NΔPanc mouse. St., stomach; Panc., pancreas; Int., intestine. The lower panels show representative H&E stainings. Scale bars: 50 μM. (I) PDAC patients were stratified for WASL expression using the UCSC Xena genomic browser, and expression levels of the indicated genes were compared. In the box plots, the whiskers represent the 5th and 95th percentile, and the central line is the median of the data, with the remaining dots being outliers. Unpaired t test with Welch’s correction.
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