EscaPI · Exploring the non-genetic (i.e. ePIgenetic) mechanisms that contribute to therapy Escape in melanoma
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-05-01 → 2022-04-30
- EU contribution
- €178,320
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Exploring the non-genetic (i.e. ePIgenetic) mechanisms that contribute to therapy Escape in melanoma
Resistance to anticancer drugs, which often develops from a heterogeneous pool of drug-tolerant cells known as minimal residual disease (MRD), is thought to mainly occur through acquisition of genetic alterations. Emerging evidence indicates that drug resistance may also be acquired in absence of a genetic cause. It remains unclear, however, whether genetic versus non-genetic mechanisms of resistance are selected in a stochastic manner, and what are the epigenomics mechanisms underlying the transition from drug-tolerance to resistance. To tackle those questions, I took advantage of scRNA-seq and scATAC-seq data generated on a melanoma PDX model displaying non-genetic resistance, at different timepoints before and during treatment with dabrafenib and trametinib. Analyzing those data, I aimed to provide a dynamic and integrated view of the evolution of transcriptional and epigenomic profiles -at single-cell resolution- before, during and after acquisition of drug resistance phenotypes in a in vivo clinically-relevant context. All together, this longitudinal study, at the level of single-cell, exploring both transcriptome and chromatin, aimed to provide precious inside about non-genetic mechanisms of resistance to therapy.
Data: CORDIS, © European Union
Project objective
Resistance to anticancer drugs, which often develops from a heterogeneous pool of drug-tolerant cells known as minimal residual disease (MRD), is thought to mainly occur through acquisition of genetic alterations. Emerging evidence indicates that drug resistance may also be acquired in absence of a genetic cause. It remains unclear, however, whether genetic versus non-genetic mechanisms of resistance are selected in a stochastic manner, and what are the epigenomics mechanisms underlying the transition from drug-tolerance to resistance. This project aims at identifying the drug-tolerant subpopulation(s) that drive non-genetic resistance by performing lineage tracing and depletion experiments in pre-clinical models. Taking advantage of up-to-date technologies combining in vivo barcoding and single-cell multi-omics approaches, this project aims to provide a dynamic and integrated view of the evolution of epigenomic profiles -at single-cell resolution- before, during and after acquisition of drug resistance phenotypes in a in vivo clinically-relevant context. A third objective of this proposal is to search for predictive biomarkers of non-genetic resistance and to assess the percentage of melanoma patients that undergo non-genetic resistance through combination of multiplexed staining and targeted DNA sequencing. The success of this project is ensured by my personal background in epigenetics and related data computational analysis, the achievements of the JCM lab in melanoma epigenetic reprogramming and the close collaborations with experts in single-cell multi-omics fields. I anticipate that my involvement in this project will broaden my skills and knowledge and help me become a high-qualified European independent scientist.
Original text from CORDIS.
Participants
- VIB VZW · ZWIJNAARDE - GENTCoordinatorBelgium
Links
Data: CORDIS, © European Union