Synthetic lethality between VPS4A and VPS4B triggers an inflammatory response in colorectal cancer.

Marta Brewińska‐Olchowik,Marta Miączyńska,Krzysztof Goryca,Magdalena Cybulska,Michał Mikula,Ewelina Szymańska,Edyta Derezińska‐Wołek,Krzysztof Kolmus,Anna Szumera‐Ciećkiewicz,Aleksandra Grochowska,Paulina Nowak,Katarzyna Piwocka,Monika Prochorec‐Sobieszek

doi:10.15252/emmm.201910812

Abstract

Somatic copy number alterations play a critical role in oncogenesis. Loss of chromosomal regions containing tumor suppressors can lead to collateral deletion of passenger genes. This can be exploited therapeutically if synthetic lethal partners of such passenger genes are known and represent druggable targets. Here, we report that VPS4B gene, encoding an ATPase involved in ESCRT‐dependent membrane remodeling, is such a passenger gene frequently deleted in many cancer types, notably in colorectal cancer (CRC). We observed downregulation of VPS4B mRNA and protein levels from CRC patient samples. We identified VPS4A paralog as a synthetic lethal interactor for VPS4B in vitro and in mouse xenografts. Depleting both proteins profoundly altered the cellular transcriptome and induced cell death accompanied by the release of immunomodulatory molecules that mediate inflammatory and anti‐tumor responses. Our results identify a pair of novel druggable targets for personalized oncology and provide a rationale to develop VPS4 inhibitors for precision therapy of VPS4B‐deficient cancers.

Highlights

Somatic copy number alterations are a key driving force in malignant transformation (Beroukhim et al, 2010)
We demonstrated that the induction of shVPS4A expression in xenografted HCT116 VPS4BÀ/À cells caused a significant retardation in tumor growth (Fig 3B)
Human cell lines were obtained from the following sources: wildtype HCT116 (HD PAR-073, HCT116 VPS4B+/+) and two CRISPR/ Cas9 engineered knockout clones (HCT116 VPS4BÀ/À) were supplied by Horizon Discovery Ltd; RKO (CRL-2577), DLD-1 (CCL221), CCD-1070Sk (CRL-2091), and CCD-841CoN (CRL-1790) cell lines were obtained from American Type Culture Collection (ATCC); HOP62 and SNU410 cell lines were from the repository of National

Summary

Introduction

Somatic copy number alterations are a key driving force in malignant transformation (Beroukhim et al, 2010). Large deletions may include loss of a tumor suppressor locus, correlating with concomitant loss of hundreds of neighboring protein-coding genes and other regulatory elements. It remains elusive whether and how these passenger alterations contribute to cancer development and progression. A synthetic lethal interaction between two genes occurs when perturbation of either gene alone does not alter cell fitness but concomitant perturbation of both genes induces a lethal phenotype This simple genetic concept underlies well-established studies that characterize functional interactions between two or more genes. Cancer research exploits this principle to develop new genotype-specific anti-cancer therapeutics (O’Neil et al, 2017) Using this approach, PARP inhibitors were introduced as a treatment option for patients with BRCA1/2-mutated tumors (Lord & Ashworth, 2017). Developing anti-cancer therapies based on this concept urgently requires identifying and characterizing novel synthetic lethal partners

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