Loss of MST/Hippo signaling in a genetically engineered mouse model of fusion-positive rhabdomyosarcoma accelerates tumorigenesis

A hallmark of fusion-positive alveolar rhabdomyosarcoma (aRMS) is the presence of a chromosomal translocation encoding the PAX3-FOXO1 fusion oncogene. Primary cell-based modeling experiments have shown that PAX3-FOXO1 is necessary, but not sufficient for aRMS tumorigenesis, indicating additional molecular alterations are required to initiate and sustain tumor growth. Previously we showed that PAX3-FOXO1-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 (Stk3F/F;Stk4F/F) mice were crossed with a previously established aRMS GEMM driven by conditional expression of Pax3:Foxo1 from the endogenous Pax3 locus and conditional loss of Cdkn2a in Myf6 (myogenic factor 6)-expressing cells. Compared to Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ controls, Stk3F/F;Stk4F/F;Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ animals displayed accelerated tumorigenesis (p<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 Pax3:Foxo1 expression and Cdkn2a 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.

https://ift.tt/2no21bl