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Epigenetic signature associated with treatment resistance in breast cancer

SIRIC team
12/07/2019
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A collaboration between the teams of A Griffith at l’ESPCI, C Vallot at SIRIC Institut Curie and A Gérard from HIFIBIO
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Deep sequencing and single cell approaches have shown that genetic heterogeneity within the tumor could be at the origin of treatment resistance (see Bellini et al Clin Cancer Res. 2015).

Céline Vallot raised the question of whether epigenetic heterogeneity could also be linked to treatment resistance. Her team studied chromatin states before and after treatment to find the answer. 

Chromatin is a structure made up of DNA, RNA and proteins called histones which influence gene expression. Depending on external stimuli, this structure can undergo chemical modifications affecting its behaviour. Genes that were initially expressed aren't anymore and vice versa. Analyzing this phenomenon at a single cell level in large cell populations within the tumor throughout treatment could help us understand as of yet unexplained treatment resistance phenomena

Using tumor models that have acquired resistance to chemotherapy and to the targeted therapy in breast cancer, the team identified a subset of cells within untreated drug-sensitive tumors that share a common chromatin signature with resistant cells. These cells have lost chromatin marks H3K27me3 which are generally associated with stable transcriptional repression for genes known to promote resistance to treatment. 

It would seem that these cells already possess characteristics that are usually specific to treatment resistance cells before treatment. 

scChIP-seq: a new high through-put sequencing approach

The discovery of Céline Vallot's team is based on a collaboration with Andrew Griffith's team at ESPCI and Annabelle Gérard from HiFiBio. The 3 teams joined forces to develop a single cell analysis technique based on droplet microfluidics. The identification of the chromatin signature would not have been possible using classic  bulk approaches. 

Overall, these results pave the way to the study of the role of chromatin heterogeneity, not only in cancer but also in other diseases and in particular during differentiation and cell development. 

Find out more about droplet microfluidics and the epigenetic study of single cells

Collaborations

The use of PDXs in the frame of this publication is the fruit of a collaboration with Elisabetta Marangoni from the Prelinical Investigation Laboratory at Institut Curie.

The SIRIC program
Examen sein
Breast cancers

Breast cancer is the most common malignant tumor in women with around 50 000 new cases diagnosed each year in France…