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1. H3K27me3 is a determinant of chemotolerance in triple-negative breast cancer

Author

Sylvain Baulande, Adeline Durand, Anne-Marie Lyne, Almut S Eisele, Pacôme Prompsy, Camille Landragin, Justine Marsolier, Ahmed Dahmani, Céline Vallot, Kevin Grosselin, Sophie Foulon, Amandine Trouchet, Sabrina Tenreira Bento, Elisabetta Marangoni, Leïla Perié, Mylène Bohec, Laura Sourd, Eric Letouzé, Léa Baudre, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), and Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, biology, [SDV]Life Sciences [q-bio], Cell fate determination, medicine.disease, 3. Good health, Chromatin, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Histone, Breast cancer, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, medicine, H3K4me3, Triple-negative breast cancer, 030304 developmental biology
Abstract

SummaryTriple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes1. Residual disease, formed by cancer cells persistent to chemotherapy, remains one of the major clinical challenges towards full cure2,3. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state4–6. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-β pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult – a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress.

Published
2021

2. CD44 regulates epigenetic plasticity by mediating iron endocytosis

Author

Bérangère Lombard, Raphaël Rodriguez, Christophe Ginestier, Tatiana Cañeque, Nicolas Servant, Emmanuelle Charafe-Jauffret, Adeline Durand, Ting-Di Wu, Céline Vallot, Anne Lafon, Damarys Loew, Sebastian Müller, Fabien Sindikubwabo, Sylvain Baulande, Antoine Versini, Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Université Paris sciences et lettres (PSL), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Rodriguez, Raphaël

Subjects
General Chemical Engineering, Iron, [SDV]Life Sciences [q-bio], Cell, Regulator, Transferrin receptor, 010402 general chemistry, Endocytosis, 01 natural sciences, Article, Epigenesis, Genetic, medicine, Humans, Epigenetics, Hyaluronic Acid, Epigenesis, biology, 010405 organic chemistry, Chemistry, CD44, General Chemistry, 0104 chemical sciences, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Histone, Hyaluronan Receptors, biology.protein
Abstract

International audience; CD44 is a transmembrane glycoprotein linked to various biological processes reliant on epigenetic plasticity, which include development, inflammation, immune responses, wound healing and cancer progression. Although it is often referred to as a cell surface marker, the functional regulatory roles of CD44 remain elusive. Here we report the discovery that CD44 mediates the endocytosis of iron-bound hyaluronates in tumorigenic cell lines, primary cancer cells and tumours. This glycan-mediated iron endocytosis mechanism is enhanced during epithelial-mesenchymal transitions, in which iron operates as a metal catalyst to demethylate repressive histone marks that govern the expression of mesenchymal genes. CD44 itself is transcriptionally regulated by nuclear iron through a positive feedback loop, which is in contrast to the negative regulation of the transferrin receptor by excess iron. Finally, we show that epigenetic plasticity can be altered by interfering with iron homeostasis using small molecules. This study reveals an alternative iron-uptake mechanism that prevails in the mesenchymal state of cells, which illuminates a central role of iron as a rate-limiting regulator of epigenetic plasticity.

Published
2020
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3. High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer

Author

Yannick Pousse, Olivia Frenoy, Adeline Durand, Adeline Poitou, Ahmed Dahmani, Adam Woolfe, Justine Marsolier, Céline Vallot, Annabelle Gérard, Fabien Reyal, Andrew D. Griffiths, Elisabetta Marangoni, Sonia Lameiras, Marcel Reichen, Kevin Grosselin, Fariba Nemati, Colin Brenan, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), Département de Recherche Translationnelle, Institut Curie [Paris], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique nucléaire et plasticité du génome (DNPG), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), HiFiBio SAS, ESPCI ParisTech, Institut Curie-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Curie, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie-Centre National de la Recherche Scientifique (CNRS)

Subjects
Chromatin Immunoprecipitation, medicine.medical_treatment, Cellular differentiation, Breast Neoplasms, Biology, Epigenesis, Genetic, Workflow, Targeted therapy, Histones, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Genetic heterogeneity, Computational Biology, High-Throughput Nucleotide Sequencing, Cancer, Microfluidic Analytical Techniques, medicine.disease, Chromatin, 3. Good health, Cell biology, Histone, biology.protein, Female, Single-Cell Analysis, Stromal Cells, Chromatin immunoprecipitation, 030217 neurology & neurosurgery
Abstract

Modulation of chromatin structure via histone modification is a major epigenetic mechanism and regulator of gene expression. However, the contribution of chromatin features to tumor heterogeneity and evolution remains unknown. Here we describe a high-throughput droplet microfluidics platform to profile chromatin landscapes of thousands of cells at single-cell resolution. Using patient-derived xenograft models of acquired resistance to chemotherapy and targeted therapy in breast cancer, we found that a subset of cells within untreated drug-sensitive tumors share a common chromatin signature with resistant cells, undetectable using bulk approaches. These cells, and cells from the resistant tumors, have lost chromatin marks-H3K27me3, which is associated with stable transcriptional repression-for genes known to promote resistance to treatment. This single-cell chromatin immunoprecipitation followed by sequencing approach paves the way to study the role of chromatin heterogeneity, not just in cancer but in other diseases and healthy systems, notably during cellular differentiation and development.

Published
2019
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