Epigenetic heterogeneity in cancer

General research interests

The Cancer Epigenetics Laboratory investigates biological processes driven by epigenetic mechanisms, focusing on the role of epigenetic regulators in cancer initiation and maintenance.

From molecules to tumours

Findings over the past 30 years have strongly implicated epigenetic mechanisms in cancer development. We now know that alterations in chromatin and DNA methylation patterns are a universal feature of the disease, that epigenetic regulators collectively are among the most mutated genes across malignancies, and that transcriptional intratumour heterogeneity shapes the organisation of many cancer types. Building on epigenomics, genomics and transcriptomics studies that have comprehensively profiled epigenome-related alterations in patients, a major goal of the laboratory is to uncover the functional impact of epigenetic deregulation in cancer and the molecular mechanisms underlying these effects. To do so, we study how epigenetics cooperate with genetics and cell-to-cell signalling in defining cancer cell behaviour at various stages of the disease. Although tissue-specific mechanisms exist and diversify cancer types, we are particularly interested in uncovering general principles underlying the role of chromatin and DNA methylation in the disease, which may be relevant for multiple solid tumours.

Our focus on cancer epigenetics has a dual rationale. Firstly, considering the intrinsic reversibility of epigenetic mechanisms and the druggable nature of many of the proteins involved in these processes, understanding how epigenetics contribute to cancer may have direct clinical implications. Secondly, elucidation of the aberrant function of epigenetic regulators in a pathological setting such as cancer may provide novel insights into their physiological role, thus increasing our knowledge of basic cell function. Driven by this motivation, we address two major questions:

•          How does epigenetic deregulation corrupt cell function during tumorigenesis?

•          How do epigenetic mechanisms contribute to generating functional diversity within tumours and influence disease progression?

To tackle these issues, we combine CRISPR-based approaches to model mutations in epigenetic regulators, genome-wide mapping methods to characterize how the epigenome responds to genetic and environmental challenges, single-cell transcriptomics and in vivo studies that allow us to evaluate the biological consequences of these alterations and explore new therapeutic opportunities.

KeywordsChromatin, epigenetic regulators, solid tumours, misregulation of gene expression, functional intratumour heterogeneity, oncogenic cellular reprogramming, cellular plasticity and adaptability, epigenetic robustness, cancer cell self-renewal, histone variants and histone modifications, epigenetic therapy.