We had initially proposed three main axes to challenge epigenomic evolution during resistance acquisition in triple negative breast cancers.
For Aim1, we had planned to characterize epigenomic evolution in in vitro and ex vivo models of patient-derived xenografts (PDX) in mice based on single cell transcriptomics and epigenomics as well as a technology to monitor phylogenies of epigenomes. We have now characterized the epigenomic and transcriptiomic identity cards of drug tolerant and resistant cells in n=10 PDX models, and identified the recurrent molecular features of drug tolerant cells in triple negative breast cancers. Part of these results were published in 2022 (Marsolier et al., Nature Genetics 2022) and in 2025 (Baudre and Jouault et al., Cancer Research 2025).
For Aim2, we had planned to monitor loci undergoing epigenomic remodeling during treatment and study the mechanisms driving drug resistance to identify compounds potentially reverting drug resistance. We have focused our efforts on understanding the role of histone demethylases and methylases in drug tolerance. We have shown that the H3K27me3 balance encodes the potential of a cancer cell to tolerate the chemotherapy treatment. In vivo, we have shown that combining chemotherapy to H3K27me3 histone demethylase inhibitors delays tumor recurrence. All theses results are published in Nature Genetics in 2022 together with the results from Aim 1. Additionally, using multiple patient-derived models to isolate persister cells, we identify the hallmarks of drug persister cells across patients and treatment regimens in TNBC: high expression of basal keratins together with activation of stress response and inflammation pathways. We identify shared transcription factors that transiently drive cells into a persister state through chromatin and enhancer reprogramming. This study provides a conceptual and experimental framework to design combination strategies that broadly target persister cells and could prevent or reverse therapy tolerance. (Baudre et al., Cancer Research 2025).
For Aim3, we had proposed to study epigenomic evolution directly in patients retrospectively, studying pairs of samples before and after treatment. We firstly optimized our single cell technologies for frozen patient biopsies, data quality was quite unsatisfactory for these challenging samples. To circumvent this problem, we developed a new method with the ability to profile rare cells with higher resolution. OneCell CUT&Tag, is a method that provides high-resolution epigenomic profiles starting from a single cell, together with full-transcriptome, surface marker quantification and protein profiling, and with low input making it uniquely adapted to study cells in small quantities like those of the rare patient-derived cells (Schwager and Moutaux et al., Biorxiv, 2026). We are now successfully producing single cell epigenomic and transcriptomic data from patent derived samples and are leading large restrospective studies.
Altogether our work resides at the forefront of cancer epigenetics, developing creative approaches to catch epigenomic mechanisms of tumor evolution in the making – both in model systems and patients. A detailed understanding of epigenomics together with genomics will be mandatory to have an impact in cancer biology, to distinguish reversible, targetable events from heritable selected traits. A global understanding of our studies fundamentals are published in Laisné, Lupien, Vallot, Nat Rev Cancer 2025.
