Defining the landscape of whole-genome doubling across mammalian tissues

About This Grant

PROJECT SUMMARY/ABSTRACT The vast majority of proliferating mammalian cells are diploid and maintain this diploid state across successive cell divisions. However, dysregulation of cell cycle controls can result in a whole-genome doubling (WGD) event, which produces a tetraploid cell with twice the normal amount of genomic and cellular material. Although some terminally differentiated cell types undergo WGD in a developmentally programmed manner, cells that experience erroneous WGD are not equipped to regulate this tetraploid state and are prone to becoming chromosomally unstable and tumorigenic. The contribution of WGD to human malignancies is significant: recent genomic analyses have revealed that a remarkable ~40% of all solid tumors have undergone at least one WGD event, often early in their development, suggesting that WGD plays a major role in the initiation and progression of human cancers. Interestingly, the frequency by which different tumors undergo WGD varies widely between tissues, suggesting that regulation of WGD in vivo is determined by tissue-specific factors. However, the causes and consequences of WGD in vivo are poorly understood due to technical limitations in identifying and isolating WGD+ cells, which are often rare, from mammalian tissues. To overcome this challenge, I have established an innovative strategy using a transgenic cell-cycle reporter mouse to enable reliable identification, purification, and manipulation of WGD+ cells from murine tissues, and I will use this approach to study the regulation of WGD in vivo. In Aim 1, I will quantify how WGD+ cells accumulate with age across different tissues and define the predominant mechanisms of WGD that occur in each tissue. In Aim 2, I will assess how the transcriptional signatures associated with WGD vary across tissues and in response to acute WGD events. Together, these aims will define the landscape of WGD in different mammalian tissues, contributing to our understanding of the mechanisms regulating the tumorigenic potential of WGD+ cells and potentially identifying new therapeutic avenues to selectively target pre-malignant or malignant WGD+ cells.