Epigenetic heterogeneity in cancer

Introduction

In many cancers, only small subsets of cells are endowed with unlimited proliferative potential and are responsible for maintaining tumour growth, whereas the rest of the cells display a more differentiated phenotype and only have limited ability to proliferate.

The molecular basis underlying the functional differences among subpopulations of tumour cells are at present unclear. We are employing genome-wide mapping approaches to characterise the chromatin landscape of self-renewing cancer cells and identify epigenetic features that distinguish them from the rest of the tumour. By combining these studies with in vivo gain- and loss-of function experiments and analysis of publicly available datasets from cancer patients, we aim to identify epigenetic features which are critical for tumour maintenance and can be modulated for therapeutic purposes. Using these approaches, we are uncovering both tumour-promoting and tumour-suppressive mechanisms that determine which cells within a tumour drive the long-term cancer growth.

A recent study investigating the molecular basis of intratumour functional heterogeneity has led to the identification of an integral component of chromatin, the linker histone H1.0, as a potent inhibitor of cancer cell self-renewal (Torres et al. Science 2016). Starting from the observation that many cancer types exhibit high intratumor heterogeneity of histone H1.0, we characterized the upstream mechanism driving reversible silencing of H1.0 in tumours, demonstrated that H1.0 heterogeneous levels define functionally distinct subsets of cells that differentially contribute to tumour maintenance, and dissected the molecular mechanism through which H1.0 affects cancer cell self-renewal. This study demonstrated that epigenetic mechanisms play a critical role in generating functional heterogeneity within tumours and can override genetic alterations that initiate the disease. It also showed that basic principles shaping tumour organisation are shared across numerous cancer types.

 

h1.0