Loss of MST/Hippo Signaling in a Genetically Engineered Mouse Model of Fusion-Positive Rhabdomyosarcoma Accelerates Tumorigenesis

Abstract

A hallmark of fusion-positive alveolar rhabdomyosarcoma (aRMS) is the presence of a chromosomal translocation encoding the fusion oncogene. Primary cell-based modeling experiments have shown that is necessary, but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously, we showed that -positive aRMS is promoted by dysregulated Hippo pathway signaling, as demonstrated by increased YAP1 expression and decreased MST activity. We hypothesized that ablating MST/Hippo signaling in a genetically engineered mouse model (GEMM) of aRMS would accelerate tumorigenesis. To this end, MST1/2-floxed ( ) mice were crossed with a previously established aRMS GEMM driven by conditional expression of from the endogenous locus and conditional loss of in (myogenic factor 6)-expressing cells. Compared with controls, animals displayed accelerated tumorigenesis ( < 0.0001) and increased tumor penetrance (88% vs. 27%). GEMM tumors were histologically consistent with aRMS. GEMM tumor-derived cell lines showed increased proliferation and invasion and decreased senescence and myogenic differentiation. These data suggest that loss of MST/Hippo signaling acts with expression and loss to promote tumorigenesis. The rapid onset and increased penetrance of tumorigenesis in this model provide a powerful tool for interrogating aRMS biology and screening novel therapeutics. A novel mouse model sheds light on the critical role of Hippo/MST downregulation in PAX3-FOXO1-positive rhabdomyosarcoma tumorigenesis. .

Signaling pathways in Rhabdomyosarcoma invasion and metastasis

“…The inhibition of MST/Hippo signaling in a genetically engineered FPRMS mouse model leads to enhanced invasion and proliferation of FPRMS tumors [102]. Yes-associated protein 1 (YAP1), a downstream effector of the Hippo pathway, has elevated expression levels in FNRMS.…”

The Emerging Role of YAP/TAZ in Tumor Immunity

“…Hippo signaling is a fundamental player in tumor biology (21)(22)(23)(24)(25)(26). MST1/2 kinases phosphorylate and activate LATS1/2, which in turn phosphorylate two transcriptional coactivators, Yes-associated protein (YAP) and WW domain-containing transcription regulator 1 (TAZ), contributing to their cytoplasmic sequestration and functional suppression (27)(28)(29)(30).…”

Discoidin Domain Receptors, DDR1b and DDR2, Promote Tumour Growth within Collagen but DDR1b Suppresses Experimental Lung Metastasis in HT1080 Xenografts

“…This effect was not observed in DDR repressed COL1 tumours, which indicated that this was an effect specifically mediated by interactions between DDRs and COL1. Loss of MST and/or LATS kinases, by either genomics deletions, epigenetic silencing or posttranslational regulation, is a characteristic of many types of sarcomas 97,99,100,103,106,[144][145][146] , which are also detected in sarcoma-derived cell lines, including in HT1080 cells 99 . Functionally, the MST/LATS kinases are considered to be tumour suppressors, and consistently genetic deletion of these kinases in mice increases tumorigenicity and the development of sarcomas 145,[147][148][149] .…”

“…The decoupling between MST/LATS kinases and YAP1 regulation observed here is consistent with evidence showing that deregulation of these kinases does not necessarily alter YAP activity (summarized in 154 ). Indeed, MST/LATS kinases can regulate downstream effector other than YAP/TAZ 104,106,145,154,155 . Conversely, YAP activity is also regulated by LATS-independent mechanisms [156][157][158] .…”