Deregulation of the Hippo pathway in soft-tissue sarcoma promotes FOXM1 expression and tumorigenesis

Significance Soft-tissue sarcomas are aggressive, often lethal tumors, which are understudied. Few therapies beyond standard resection and traditional chemotherapy/radiation are available. Sarcomas are diverse malignancies, including ∼65 distinct histological subtypes. The existence of common mechanisms underlying multiple subtypes has not previously been shown. We demonstrate that the Hippo pathway, an important regulator of cell proliferation, is deregulated in ≥25% of sarcomas, encompassing multiple commonly diagnosed subtypes. When control of the Hippo pathway is lost, expression of the effector protein Yes-Associated Protein (YAP) is stabilized, resulting in higher levels of proliferation. For the first time, to our knowledge, we show that YAP interacts with the forkhead box transcription factor FOXM1 to coregulate critical components of sarcomagenesis, specifically in fibrosarcoma, undifferentiated pleomorphic sarcomas, and liposarcomas. Genetic aberrations responsible for soft-tissue sarcoma formation in adults are largely unknown, with targeted therapies sorely needed for this complex and heterogeneous family of diseases. Here we report that that the Hippo pathway is deregulated in many soft-tissue sarcomas, resulting in elevated expression of the effector molecule Yes-Associated Protein (YAP). Based on data gathered from human sarcoma patients, a novel autochthonous mouse model, and mechanistic analyses, we determined that YAP-dependent expression of the transcription factor forkhead box M1 (FOXM1) is necessary for cell proliferation/tumorigenesis in a subset of soft-tissue sarcomas. Notably, FOXM1 directly interacts with the YAP transcriptional complex via TEAD1, resulting in coregulation of numerous critical pro-proliferation targets that enhance sarcoma progression. Finally, pharmacologic inhibition of FOXM1 decreases tumor size in vivo, making FOXM1 an attractive therapeutic target for the treatment of some sarcoma subtypes.

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