Abstract A08: Loss of noncanonical Hippo signaling in fusion-positive alveolar rhabdomyosarcoma increases invasiveness and a dedifferentiated phenotype associated with metastasis
Oristian, KM; Crose, LES; Kuprasertkul, N; Bentley, RC; Lin, Y-T; Williams, N; Kirsch, DG; Linardic, CM
Published in: Molecular Cancer Research
A hallmark of alveolar rhabdomyosarcoma (ARMS) is the presence of a chromosomal translocation encoding the PAX3-FOXO1 fusion oncogene (FP-ARMS). Patients presenting with FP-ARMS represent the subset of rhabdomyosarcoma patients with the worst prognosis, and when metastatic, survival for these children and adolescents is less than 10%. Nevertheless, standard of care has not changed in the clinic in decades due to a lack of novel effective therapeutics, and as a result, efforts are ongoing to develop better models of this disease in vivo and identify new and more predictive biomarkers. Recently, our group identified a role for Hippo/MST signaling in a genetically engineered mouse model (GEMM) of FP-ARMS that demonstrates Stk3F/F;Stk4F/F; Pax3PF/PF;Cdkn2aF/F;Myf6ICN/+ ARMS tumor-derived cells are less differentiated and more invasive in vitro as compared to Pax3PF/PF;Cdkn2aF/F; Myf6ICN/+ counterparts. Preliminary in vivo studies show that FP-ARMS GEMM tumor-derived cells form secondary metastases in both the lungs and livers of recipient animals, suggesting a new utility of the model for studies of metastatic potential. Studies of bone marrow metastasis, a lethal disease progression in PF-ARMS patients, are ongoing. Further, canonical signaling down the kinase cascade from MST1/2 to YAP1 is largely unchanged in this model, implicating instead noncanonical Hippo signaling and a potential role for MOB1, a Hippo pathway modulator implicated in mitotic exit and expressed highly in the bone marrow niche. Together, these data present an opportunity to interrogate the biology driving the predisposition of PF-RMS patients to develop metastases, and a foundation to identify novel preclinical targets.Citation Format: Kristianne M. Oristian, Lisa E.S. Crose, Napasorn Kuprasertkul, Rex C. Bentley, Yi-Tzu Lin, Nerissa Williams, David G. Kirsch, Corinne M. Linardic. Loss of noncanonical Hippo signaling in fusion-positive alveolar rhabdomyosarcoma increases invasiveness and a dedifferentiated phenotype associated with metastasis [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A08.
