METCLL SIGNED
Discovery and validation of ‘epidrivers’ of cancer evolution and resistance to therapy
Total Cost €
0EC-Contrib. €
0Partnership
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Explore the words cloud of the METCLL project. It provides you a very rough idea of what is the project "METCLL" about.
Project "METCLL" data sheet
The following table provides information about the project.
| Coordinator |
INSTITUT CURIE
Organization address contact info |
| Coordinator Country | France [FR] |
| Total cost | 264˙668 € |
| EC max contribution | 264˙668 € (100%) |
| Programme |
1. H2020-EU.1.3.2. (Nurturing excellence by means of cross-border and cross-sector mobility) |
| Code Call | H2020-MSCA-IF-2016 |
| Funding Scheme | MSCA-IF-GF |
| Starting year | 2018 |
| Duration (year-month-day) | from 2018-09-01 to 2021-08-31 |
Partnership
Take a look of project's partnership.
| # | ||||
|---|---|---|---|---|
| 1 | INSTITUT CURIE | FR (PARIS) | coordinator | 264˙668.00 |
| 2 | CORNELL UNIVERSITY | US (ITHACA NY) | partner | 0.00 |
Map
Project objective
Intra-tumoral heterogeneity allows all form of cancers to undergo an evolutionary process in response to selective pressures, such as therapy, which results in a more aggressive disease. As chronic lymphocytic leukemia (CLL) are particularly amenable to evolutionary investigations, it has been shown that CLL’s capacity to escape therapy is linked in to genetic evolution, which is fueled by intra-tumoral heterogeneity. Aberrant DNA methylation can also dysregulates genes involved in CLL pathogenesis. Like genetic alterations, DNA methylation modifications are heritable and subject to natural selection. Landau et al have studied sub-population DNA methylation heterogeneity in CLL and uncovered a large amount of stochastic variation. The acquisition of stochastic DNA methylation alterations enhances epigenetic plasticity and creates a non–genetically encoded source of heterogeneity, fuelling tumour cells in their search for superior evolutionary trajectories. These new data modify the way we understand cancer epigenetics, and offer a new field of investigation: identify “epidrivers”, i.e. somatic epigenetic alterations leading to cancer-heterogeneity and which are positively selected through cancer evolution. Thus, I will pursue in this project four independent yet complementary aims. During my outgoing period I will robustly identify epidrivers from bulk next-generation sequencing (NGS) (Aim 1) and from single-cell NGS (Aim 2) of a large CLL cohort. Candidate epidrivers uncovered from the first two aims, will be further validated in a large-scale epigenome editing screen (Aim 3). Then building upon technological development from Aim 2 and 3, during my returning period at Curie Institute, I will extend this important paradigm to solid tumor by exploring breast cancer evolution (Aim 4). This integrative analysis of epigenetic heterogeneity will enable the reconstruction of tumor epigenetic population complexity and how it shapes disease relapse and evolution.
Publications
| year | authors and title | journal | last update |
|---|---|---|---|
| 2019 |
Anna S. Nam, Kyu-Tae Kim, Ronan Chaligne, Franco Izzo, Chelston Ang, Justin Taylor, Robert M. Myers, Ghaith Abu-Zeinah, Ryan Brand, Nathaniel D. Omans, Alicia Alonso, Caroline Sheridan, Marisa Mariani, Xiaoguang Dai, Eoghan Harrington, Alessandro Pastore, Juan R. Cubillos-Ruiz, Wayne Tam, Ronald Hoffman, Raul Rabadan, Joseph M. Scandura, Omar Abdel-Wahab, Peter Smibert, Dan A. Landau Somatic mutations and cell identity linked by Genotyping of Transcriptomes published pages: 355-360, ISSN: 0028-0836, DOI: 10.1038/s41586-019-1367-0 |
Nature 571/7765 | 2020-01-21 |
| 2019 |
Federico Gaiti, Ronan Chaligne, Hongcang Gu, Ryan M. Brand, Steven Kothen-Hill, Rafael C. Schulman, Kirill Grigorev, Davide Risso, Kyu-Tae Kim, Alessandro Pastore, Kevin Y. Huang, Alicia Alonso, Caroline Sheridan, Nathaniel D. Omans, Evan Biederstedt, Kendell Clement, Lili Wang, Joshua A. Felsenfeld, Erica B. Bhavsar, Martin J. Aryee, John N. Allan, Richard Furman, Andreas Gnirke, Catherine J. Wu, Alexander Meissner, Dan A. Landau Epigenetic evolution and lineage histories of chronic lymphocytic leukaemia published pages: , ISSN: 0028-0836, DOI: 10.1038/s41586-019-1198-z |
Nature | 2020-01-21 |
| 2019 |
Alessandro Pastore, Federico Gaiti, Sydney X. Lu, Ryan M. Brand, Scott Kulm, Ronan Chaligne, Hongcang Gu, Kevin Y. Huang, Elena K. Stamenova, Wendy Béguelin, Yanwen Jiang, Rafael C. Schulman, Kyu-Tae Kim, Alicia Alonso, John N. Allan, Richard R. Furman, Andreas Gnirke, Catherine J. Wu, Ari M. Melnick, Alexander Meissner, Bradley E. Bernstein, Omar Abdel-Wahab, Dan A. Landau Corrupted coordination of epigenetic modifications leads to diverging chromatin states and transcriptional heterogeneity in CLL published pages: , ISSN: 2041-1723, DOI: 10.1038/s41467-019-09645-5 |
Nature Communications 10/1 | 2020-01-21 |
| 2019 |
Ronan Chaligne, Anna S. Nam, Dan A. Landau TARGET-seq Takes Aim at Cancer Evolution through Multi-omics Single-Cell Genotyping and Transcriptomics published pages: 1092-1094, ISSN: 1097-2765, DOI: 10.1016/j.molcel.2019.03.009 |
Molecular Cell 73/6 | 2020-01-21 |
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