Research areas
Our focus on cancer epigenetics has a dual rationale. Firstly, given the inherent 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?
Oncogenic reprogramming
Tumour initiation entails loss of cellular identity and acquisition of aberrant cellular capabilities. We are interested in studying how disruption of epigenetic control promotes this cellular reprogramming process. We employ CRISPR-based technologies and single cell analysis to interrogate proteins involved in the establishment and recognition of DNA methylation patterns, writer, readers and erasers of chromatin marks, chromatin remodelers and proteins controlling the high-order structure of chromatin, in order to identify epigenetic regulators which either prevent (tumour suppressors) or promote (therapeutic targets) tumorigenesis. We are also interested in characterizing how changes in the epigenome mediate the effect of classical oncogenes and understand how cellular transformation corrupts the function of many wild-type epigenetic regulators and subverts developmental transcriptional programs.
Functional intratumour heterogeneity
Despite the clonal nature of cancer, individual tumors are characterized by remarkable heterogeneity at all levels: genetic subclones emerge and evolve independently during tumor growth; various transcriptional states co-exist and adapt in response to changing environment; protein repertoires and epigenetic landscapes vary depending on intrinsic and extrinsic factors. Altogether, these alterations result in intratumor functional heterogeneity, with distinct subsets of cells contributing differently to tumor maintenance, progression and response to therapy. We combine genetic, genomic and imaging approaches with functional in vivo assays to dissect how epigenetic alterations contribute to generating functional diversity within tumors, and to understand how we can interfere with this process. In a recent study, we have identified phenotypic inertia as a novel mechanism promoting the expansion of epigenetically-disrupted subclones, which drives cancer evolution across cancer types (Loukas et al. Cancer Cell 2023). We are now expanding our investigation to therapy-induced cancer evolution. Using next-generation molecular barcoding, we aim to identify epigenetic feature that predispose subset of cancer cells to survive therapy and drive disease relapse.
Compromised epigenetic robustness and vulnerabilities to epigenetic drugs
As a group, genes encoding epigenetic regulators are among the most mutated genes in cancer. The prevalence of these mutations across all cancer types is one of the most surprising findings from recent cancer genomics studies, yet our understanding of how they promote the disease is still limited. In parallel lines of investigations, we are studying how cumulative disruption of epigenetic control - at the network level - favours cancer development, and how the resulting reduction in network robustness creates synthetic lethal vulnerabilities that we can exploit to interfere with the disease. To do so, we employ genome editing to mimic the genetic alterations often observed in patients, in vitro and in vivo functional assays to examine cancer cell behaviour, and single cell transcriptomic analysis to dissect how cells buffer perturbations in various contexts. Experimental investigation is complemented by advanced computational analysis and machine learning approaches aimed at predicting cellular and patient response to epigenetic therapy. We are particularly interested in understanding (i) the basis of epigenetic robustness in normal cells and how this is compromised in cancer; (ii) the functional consequences of destabilizing the network of epigenetic regulators at various stages of the disease; (iii) whether we can predict epigenetic vulnerabilities based on how the regulatory network is disrupted in a patient.