Periodic Reporting for period 2 - ChromTrace (Tracing epigenetic evolution of triple-negative breast cancer towards chemo-resistance)
Periodo di rendicontazione: 2022-07-01 al 2023-12-31
The emergence of resistance to chemotherapy and targeted therapies is a major challenge for the treatment of cancer. If patients respond to initial treatments, they can in some cases relapse, with some cancer cells resistant to therapies driving the recurrence. In breast cancers, such resistance mechanisms particularly occur in triple negative breast cancers that can often recur after initial response to chemotherapies. While several genetic mechanisms driving resistance processes have been discovered, non-genetic mechanisms have also been shown to contribute to therapy resistance. In the ChromTrace project, we focus on epigenomic mechanisms of resistance to treatment, that rather involve chemical modifications of DNA and its proteins than mutations of the DNA sequence itself. So far, our restricted understanding of epigenomic evolution has 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 cancers, chemotherapy is the standard of care, but chemo-resistance remains the major unmet clinical need.
In this project, we are exploring the heterogeneity of chromatin states - key determinant of cell identity - in tumor cells, studying how they are transmitted and determining whether they are driving the resistance phenotype. To do so, we develop single cell approaches to monitor the phylogeny of epigenomic modifications, ie how cells change and transmit epigenomic features under treatment exposure. Understanding 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.
In this project, we are exploring the heterogeneity of chromatin states - key determinant of cell identity - in tumor cells, studying how they are transmitted and determining whether they are driving the resistance phenotype. To do so, we develop single cell approaches to monitor the phylogeny of epigenomic modifications, ie how cells change and transmit epigenomic features under treatment exposure. Understanding 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.
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).
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 the results of this aim have been published in Nature Genetics in 2022 together with the results from Aim 1.
For Aim3, we had proposed to study epigenomic evolution directly in patients retrospectively, studying pairs of samples before and after treatment. To do so, we first need to optimize our single cell technologies for frozen patient biopsies. We have now successfully produced single cell epigenomic and transcriptomic data from such samples and are leading large restrospective studies.
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).
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 the results of this aim have been published in Nature Genetics in 2022 together with the results from Aim 1.
For Aim3, we had proposed to study epigenomic evolution directly in patients retrospectively, studying pairs of samples before and after treatment. To do so, we first need to optimize our single cell technologies for frozen patient biopsies. We have now successfully produced single cell epigenomic and transcriptomic data from such samples and are leading large restrospective studies.
Our demonstration that combination of epigenetic drugs can increase the response to chemotherapy in triple negative breast cancers in my view advances our understanding of cancer. We demonstrate that the earliest steps in the acquisition of drug resistance are non genetic, and that combining histone demethylase inhibitors can prevent drug tolerance, and increase disease free survival. Such results were beyond state of the art as they rely on cutting edge epigenomic and lineage tracing strategies. These findings have implications for the management of drug resistance, and how we could prevent cells from escaping the initial treatment effect. We are now further investigating how to best target histone demethylase for future therapeutic strategies.