Tracing epigenetic evolution of triple-negative breast cancer towards chemo-resistance

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The emergence of resistance to chemotherapy and targeted therapies is a major challenge for the treatment of cancer. While several genetic mechanisms driving resistance processes have been discovered, non-genetic mechanisms have also been shown to contribute to drug resistance. Yet, our restricted understanding of epigenetic evolution has so far limited our ability to modulate resistance using epigenetic modifiers. With ChromTrace, our goal is to reconstruct and define the contribution of epigenetic evolution to chemo-resistance in triple-negative breast tumors. In this aggressive sub-type of breast cancer, chemotherapy is the standard of care, but chemo-resistance remains the major unmet clinical need. We will explore the heterogeneity of H3K27me3chromatin states - key determinant of cell identity - in tumor cells, study how they are transmitted and determine whether they are associated to the resistance phenotype. Combining lineage tracing and targeted sequencing to our original single-cell chromatin profiling approach, we will reconstruct the dynamics of chromatin features over time in the context of genetic evolution. In parallel, using a live-cell microscopy reporter system, we will evaluate the association of recurrent chromatin features with the resistance phenotype and elucidate mechanisms of epigenetic tumor evolution. Our results on the heritability and plasticity of chromatin landscapes will have strong impact on our understanding of epigenetic evolution in cancer. Our long-term goal is to build on this integrated appreciation of molecular tumor evolution processes to propose novel therapeutic strategies to control resistance to chemotherapy. Finally, our approaches being applicable to any dynamic biological system, ChromTrace opens the perspective to study evolution of chromatin landscapes not only in other types of cancer and disease, but also during normal development.