Wednesday, February 5, 2025
2/5/2025
Chromosome instability (CIN), broadly defined as the persistent acquisition of both numerical and structural chromosome aberrations, is a hallmark of solid tumors that is known to facilitate tumor initiation, progression, and relapse. Consequently, CIN confers poor clinical prognosis. The development of CIN is a multistep process: cells must not only acquire the genetic and/or cell biological defects that induce abnormal chromosome segregation, but they must also overcome the stresses imposed by aneuploidy that act to restrain subsequent proliferation. Over the past decade, significant efforts have focused on identifying the underlying mechanisms that produce chromosome missegregation in cancer cells. However, there remains a paucity of data describing the mechanisms that respond to abnormalities in chromosome number and limit proliferation. Consequently, how cells adapt to overcome these growth barriers in order to become CIN remains a key unresolved question in cancer cell biology. We recently discovered that the Hippo tumor suppressor pathway is activated following cytokinesis failure and that this limits the proliferation of the resulting tetraploid cells. In addition, our preliminary data suggest that inactivation of Hippo signaling is sufficient to promote CIN in non-transformed cells. Together, these findings suggest that the Hippo pathway may have a broadly relevant role in restraining the growth of cells harboring numerical chromosome abnormalities. The goal of this proposal is to elucidate the mechanistic role of the Hippo pathway in both sensing and responding to abnormal cell division and aneuploidy. The aims are: 1) To mechanistically define the role of the Hippo pathway in maintaining chromosome stability; 2) To determine the role of Hippo signaling in setting the mitotic clock; and 3) To identify cancer-relevant genetic regulators of Hippo pathway signaling.
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