Cellular plasticity and Epigenetics
Relapse after the initial treatment is often attributed to pre-existing intratumoral heterogeneity, resulting in therapy resistant subpopulations that expand after treatment. While therapy resistance is frequently associated with the acquisition of additional genetic mutations, there are also non-genetic mechanisms that underlie relapse and give rise to cell state transitions. These cell state transitions otherwise known as cellular plasticity, can give rise to therapy resistant subpopulations. The key question driving our team is how pediatric cancers relapse after therapy, despite having much fewer genetic aberrations than cancers occurring in adults. We propose that the answer lies in non-genetic mechanisms driving cellular plasticity—most notably, the relatively understudied epigenome.
Our research
Our methodology of choice to identify epigenetic patterns underlying cellular plasticity is scalable single cell methylation sequencing to acquire both the DNA methylation profiles and genetic information of single cells. The strategy allows us to study both genetic and epigenetic events simultaneously to trace how cell states, subclones and their corresponding epigenetic states expand or retract. We create single cell atlases to inform how cell states and epigenetic profiles are shaped in response to therapy.
We also study epigenetic patterns and mechanisms underlying plasticity by modulating key epigenetic modifiers to model plasticity. Modelling the transitions that would occur in tumors allows us to comprehend the epigenetic mechanisms behind cell state transitions. A better understanding of how these cell state transitions occur enables us to investigate whether the transitions can be prevented or reversed with the goal to inform novel therapy.
By identifying epigenetic patterns of individual cells, we also acquire the ability to train machine learning models on epigenetic states of distinct cellular subpopulations. The onset of methylation-based classification of pediatric tumors has demonstrated the utility and robustness of methylation data as a biomarker in the clinic. We aim to extend the use of epigenetic patterns to routinely detect the occurrence of cellular plasticity and potential therapeutic vulnerabilities.
Together, our research aims to enhance our understanding of the epigenetic patterns involved in therapy resistance, particularly those involved in cellular plasticity, with the long-term goal of translating these findings to advance personalized patient care.