Researchers Identify Tumor Suppressor Pathway that Monitors Chromosome Number
The Laboratory of Cancer Cell Biology has identified the tumor suppressor mechanism that prevents the oncogenic growth of cells harboring an abnormal number of chromosomes. The study, published in the journal Cell, was led by Neil J. Ganem, PhD.
Tetraploid cells, which are a common byproduct of cell division failure, are genomically unstable and have the capacity to facilitate tumorigenesis. Recent estimates suggest that ~40% of all solid tumors have undergone a transient tetraploid intermediate at some point during their evolution, suggesting that tetraploidy plays significant roles in both the development and/or progression of human malignancies. Given the potentially oncogenic consequences of tetraploidy, it is not surprising that tumor suppression mechanisms have evolved that prevent the proliferation of these cells. However, unlike other common cellular insults that trigger cell cycle arrest, such as DNA damage, the mechanisms governing cell cycle arrest in response to tetraploidy have been poorly defined.
To understand the mechanism of growth arrest in tetraploid cells, Dr. Ganem and colleagues combined genome-wide RNAi screening and in vitro evolution approaches to comprehensively identify all of the genes required to stall the growth of tetraploid cells. Collectively, these data revealed that the Hippo tumor suppressor pathway is specifically activated in tetraploid cells, both in vitro and in vivo, and that this is the pathway that prevents tetraploid proliferation. The authors pinpointed that defects in the cytoskeleton of tetraploid cells represented the initial trigger for Hippo pathway activation. Notably, analysis of a broad spectrum of human cancers revealed that near-tetraploid tumors frequently adapt to overcome Hippo signaling, suggesting that inactivation or bypass of this pathway may be a prerequisite for the development of high-ploidy tumors. “This work may help guide the development of new therapies that specifically target tumor cells with abnormal numbers of chromosomes, while sparing the normal healthy cells from which they originated,” explained corresponding author Dr. Ganem, PhD, Assistant Professor of Pharmacology & Experimental Therapeutics and Medicine in the Shamim and Ashraf Dahod Breast Cancer Research Laboratories at BUSM.
The study was highlighted with a preview article in Cell and by the journals Science Signaling, Cancer Discovery, and Nature Reviews Cancer. The article can be read online at: http://www.cell.com/cell/abstract/S0092-8674(14)00820-4.