Genetic Alterations and Deregulation of Hippo Pathway as a Pathogenetic Mechanism in Bone and Soft Tissue Sarcoma

SIMPLE SUMMARY: Cancer is a genetic disease that is caused by changes in genes controlling cell growth, migration, and differentiation. Usually, cancer cells hijack processes used by healthy cells during organism development. The Hippo pathway is a developmental signaling system with a critical role in tissue and organ size regulation, which is frequently deregulated in cancer. Indeed, the contribution of Hippo dysfunction to cancer development has been extensively reported in carcinomas, but it is increasingly recognized in sarcomas. Sarcomas are rare cancers that develop in the bones and soft tissues, encompassing a large variety of different subtypes. Here we review the relevance of the Hippo pathway in specific sarcoma subtypes, with a focus on both the genetic alterations in Hippo pathway genes as well as other molecular mechanisms involved in its deregulation. ABSTRACT: The Hippo pathway is an evolutionarily conserved modulator of developmental biology with a key role in tissue and organ size regulation under homeostatic conditions. Like other signaling pathways with a significant role in embryonic development, the deregulation of Hippo signaling contributes to oncogenesis. Central to the Hippo pathway is a conserved cascade of adaptor proteins and inhibitory kinases that converge and regulate the activity of the oncoproteins YAP and TAZ, the final transducers of the pathway. Elevated levels and aberrant activation of YAP and TAZ have been described in many cancers. Though most of the studies describe their pervasive activation in epithelial neoplasms, there is increasing evidence pointing out its relevance in mesenchymal malignancies as well. Interestingly, somatic or germline mutations in genes of the Hippo pathway are scarce compared to other signaling pathways that are frequently disrupted in cancer. However, in the case of sarcomas, several examples of genetic alteration of Hippo members, including gene fusions, have been described during the last few years. Here, we review the current knowledge of Hippo pathway implication in sarcoma, describing mechanistic hints recently reported in specific histological entities and how these alterations represent an opportunity for targeted therapy in this heterogeneous group of neoplasm.