An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields

Simple Summary: Although research on cancer biology in recent decades has unveiled the main genetic perturbations driving the onset of tumorigenesis, we are still far from properly treating this disease without the occurrence of drug resistance and metastatic burden. This achievement is hampered by the onset of intra-tumour heterogeneity (ITH), which increases cancer cell fitness and plasticity, thereby fostering cell adaptation to foreign environments and stimuli. In this review, we discuss the contribution of the epigenetic factors in sustaining ITH and their interplay with the tumour microenvironment. We also highlight the recent technological advancements that are contributing to defining the epigenetic mechanisms governing tumour heterogeneity at the single-cell level. Cancer is a group of heterogeneous diseases that results from the occurrence of genetic alterations combined with epigenetic changes and environmental stimuli that increase cancer cell plasticity. Indeed, multiple cancer cell populations coexist within the same tumour, favouring cancer progression and metastatic dissemination as well as drug resistance, thereby representing a major obstacle for treatment. Epigenetic changes contribute to the onset of intra-tumour heterogeneity (ITH) as they facilitate cell adaptation to perturbation of the tumour microenvironment. Despite being its central role, the intrinsic multi-layered and reversible epigenetic pattern limits the possibility to uniquely determine its contribution to ITH. In this review, we first describe the major epigenetic mechanisms involved in tumourigenesis and then discuss how single-cell-based approaches contribute to dissecting the key role of epigenetic changes in tumour heterogeneity. Furthermore, we highlight the importance of dissecting the interplay between genetics, epigenetics, and tumour microenvironments to decipher the molecular mechanisms governing tumour progression and drug resistance.