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METCLL SIGNED

Discovery and validation of ‘epidrivers’ of cancer evolution and resistance to therapy

Total Cost €

0

EC-Contrib. €

0

Partnership

0

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 METCLL project word cloud

Explore the words cloud of the METCLL project. It provides you a very rough idea of what is the project "METCLL" about.

enhances    evolutionary    chronic    outgoing    period    tumoral    dysregulates    pressures    tumor    genetically    heritable    paradigm    cohort    understand    methylation    generation    pathogenesis    first    building    sub    landau    cll    shapes    data    undergo    capacity    reconstruction    cancers    fuelling    modifications    search    dna    uncovered    subject    shown    amount    technological    candidate    fueled    intra    breast    genetic    epidrivers    independent    heterogeneity    escape    validated    alterations    cancer    superior    complexity    epigenetic    epigenetics    complementary    curie    aggressive    linked    somatic    relapse    sequencing    integrative    leukemia    ngs    encoded    cells    robustly    acquisition    trajectories    extend    variation    aberrant    creates    solid    stochastic    tumour    selective    et    amenable    editing    source    genes    form    therapy    epigenome    investigations    modify    single    returning    bulk    pursue    investigation    population    disease    al    evolution    plasticity    lymphocytic    cell    positively    exploring    natural    screen   

Project "METCLL" data sheet

The following table provides information about the project.

Coordinator
INSTITUT CURIE 

Organization address
address: rue d'Ulm 26
city: PARIS
postcode: 75231
website: www.curie.fr

contact info
title: n.a.
name: n.a.
surname: n.a.
function: n.a.
email: n.a.
telephone: n.a.
fax: n.a.

 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.

# participants  country  role  EC contrib. [€] 
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
List of publications.
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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