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.
A hallmark of human cancer cells is that they possess an aberrant number of chromosomes, a defect that is known to facilitate tumor initiation, progression, and relapse. The aims of this proposal are designed to illuminate the mechanisms by which cancer cells acquire an abnormal complement of chromosomes. This work has the potential to reveal new therapeutic avenues that selectively kill cancer cells while sparing the normal cells from which they originated.
| Vittoria, Marc A; Shenk, Elizabeth M; O'Rourke, Kevin P et al. (2018) A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation. Mol Biol Cell 29:1682-1692 |
| Grant, Trevor J; Mehta, Anita K; Gupta, Anamika et al. (2017) STK38L kinase ablation promotes loss of cell viability in a subset of KRAS-dependent pancreatic cancer cell lines. Oncotarget 8:78556-78572 |
| Lim, Sanghee; Quinton, Ryan J; Ganem, Neil J (2016) Nuclear envelope rupture drives genome instability in cancer. Mol Biol Cell 27:3210-3213 |
