Synthetic lethality between VPS 4A and VPS 4B triggers an inflammatory response in colorectal cancer

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.

Concurrent depletion of Vps37 proteins evokes ESCRT-I destabilization and profound cellular stress responses

“…Differential expression of 57 genes was common across stages of tumorigenesis, whereas 43 and 12 genes were unique for early and advanced stages, respectively (Table S2). In addition to decreased mRNA abundance of VPS4B, which we studied previously (Szymanśka et al, 2020), we detected reduced expression of an ESCRT-I component -VPS37Bin advanced stage CRC (Fig. 1C).…”

“…The advent of next-generation sequencing technologies has permitted unbiased screening of components orchestrating receptor transport and endolysosomal degradation in distinct pathological settings (Buser et al, 2019;Yoshida et al, 2010). Here, by mining RNA-Seq datasets we revealed differential expression of 112 endocytic machinery components across stages of CRC, several of which were previously shown to be reduced in adenocarcinoma (Kwong et al, 2005;Szymanśka et al, 2020;Tanigawa et al, 2019). In-depth validation of our in silico screen uncovered reduced mRNA and protein abundance of VPS37A and VPS37B paralogs in CRC patients.…”

“…For instance, we previously demonstrated that the expression of VPS4B, encoding an ESCRTassociated ATPase, is decreased in colorectal cancer (CRC), and VPS4B-deficient cells are critically dependent on the Vps4A protein. This synthetic lethality between VPS4 paralogs triggers stress-associated sterile inflammatory response and immunogenic cell death and thus may be used as a basis for personalized therapy (Szymanśka et al, 2020).…”

Vaccinia virus hijacks ESCRT-mediated multivesicular body formation for virus egress

“…Although our screen suggested that VPS4A was required for VACV spread, as VPS4B was not targeted in the screen, follow-up individual depletion experiments were performed which indicated that VPS4B was rather the critical factor. These experiments revealed that, in HeLa cells, the relative abundance of VPS4A and VPS4B is markedly different, and that a complex compensatory relationship may exist between these paralogs-consistent with findings in yeast and cancer cells (Scheuring et al, 2001;Szymańska et al, 2020).…”

Exosomal Components and Modulators in Colorectal Cancer: Novel Diagnosis and Prognosis Biomarkers

“…Additionally, these altered expression profiles also persist in the metastatic cancer cells. In contrast, Vps4-Vta1 and ALIX act as gatekeepers to terminate exocytosis and, therefore, their function is often suppressed in malignant colorectal tumors [45,46]. Most RABs show excessive expression, coordinating the production and transportation of EVs, but there are also some redundant trends (Table 1).…”