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1. H3K27me3 conditions chemotolerance in triple-negative breast cancer

Author

Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, Amandine Trouchet, Sabrina Tenreira Bento, Almut Eisele, Sophie Foulon, Léa Baudre, Kevin Grosselin, Mylène Bohec, Sylvain Baulande, Ahmed Dahmani, Laura Sourd, Eric Letouzé, Anne-Vincent Salomon, Elisabetta Marangoni, Leïla Perié, Céline Vallot, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Recherche Translationnelle, Institut Curie [Paris], Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), HiFiBiO Therapeutics SAS [Paris], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Plateforme de Séquençage ADN haut débit [Institut Curie] (NGS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the ATIP Avenir program, by Plan Cancer, by the SiRIC-Curie program SiRIC Grants #INCa-DGOS-4654 and #INCa-DGOS-Inserm_12554, and by a starting ERC grant from the H2020 program #948528-ChromTrace (to CV), and by the Fondation de France #00107944 (to JM). The work was supported by an ATIP-Avenir grant from CNRS and Bettencourt-Schueller Foundation, by a starting ERC grant from the H2020 program #758170-Microbar (to LP). And by the SiRIC-Curie program SiRIC Grant #INCa-DGOS- 4654., ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Perié, Leïla, Des cellules aux tissus: au croisement de la Physique et de la Biologie - - CelTisPhyBio2011 - ANR-11-LABX-0038 - LABX - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
Histones, [SDV] Life Sciences [q-bio], Breast cancer, Drug Resistance, Neoplasm, Lysine, [SDV]Life Sciences [q-bio], Genetics, Humans, Triple Negative Breast Neoplasms, Epigenetics, Neoplasm Recurrence, Local, Methylation
Abstract

International audience; The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.

Published
2022
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2. High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics

Author

Andrew D. Griffiths, Alexei Godina, Guillaume Mottet, Gaël A. Millot, Bingqing Shen, Samantha N. Stewart, Vera Menrath, Sosthene Essono, Baptiste Saudemont, Clément Nizak, Annabelle Gérard, Antoine Sautel-Caillé, Scott McNamara, Matthieu Delince, Sami Ellouze, Jean Baudry, Marcel Reichen, Pablo Canales-Herrerias, Charina Ortega, Patrick England, Carlos Castrillon, Odile Richard-Le Goff, Colin Brenan, Klaus Eyer, Pascaline Mary, Luis Briseño-Roa, Allan Jensen, Pierre Bruhns, Raphael Clement Li-Ming Doineau, Adam Woolfe, Roshan Kumar, Bin Jia, Bruno Iannascoli, Yannick Pousse, Kevin Grosselin, Gregory Rose, Adeline Poitou, HiFiBiO Therapeutics SAS [Paris], Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Doctorale Frontières du Vivant - Programme Bettencourt (FdV), Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité, Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Colloïdes et Matériaux Divisés (LCMD), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), HiFiBiO Therapeutics Inc. [Cambridge], Abbvie Bioresearch Center [Worcester], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biophysique Moléculaire (Plate-forme), Biophysique des macromolécules et leurs interactions, This work was supported by the French Agence Nationale de la Recherche (ANR-14-CE16-0011 project DROPmAbs), by the Centre d’Innovation et Recherche Technologique (Citech) through the Institut Carnot Pasteur Microbes & Santé (ANR 16 CARN 0023-01), by BPI France (OSIRIS and CELLIGO projects) and by the French ‘Investissements d’Avenir’ program via the CELLIGO project and grant agreements ANR-10-NANO-02, ANR-10-IDEX-0001-02 PSL, ANR-10-LABX-31 and ANR-10-EQPX-34. NGS was performed by the ICGex NGS platform of the Institut Curie and the Institut de Biologie Intégrative de la Cellule (I2BC) platform (Gif-sur-Yvette) supported by the grants ANR-10-EQPX-03 and ANR-10-INBS-09-08 (France Génomique Consortium), by the Canceropole Ile-de-France and by the SiRIC-Curie program (SiRIC Grant INCa-DGOS- 4654). C.C. acknowledges financial support from CONCYTEC, Peru. P.C.H. is a scholar in the Pasteur - Paris University (PPU) International PhD program and was also supported by the Fondation pour la Recherche Médicale (FRM, FDT201904008240). K.E. acknowledges financial support from the Swiss National Science Foundation and The Branco Weiss Fellowship - Society in Science., We would like to thank M. Holsti and W. Somers (Pfizer, BioMedicine Design) for advice on the technology development and critical reading of the manuscript, R. Nicol (Whitehead Institute, MIT Center for Genome Research) for advice on barcoded sequencing, at the Institut Pasteur, H. Mouquet for advice on antibody sequence selection, and F. Jönsson for advice on flow cytometry analysis, T. Kirk and S. Foulon (ESPCI Paris) for their help developing the barcoded hydrogel beads, S. N. Stewart (HiFiBio Therapeutics Inc.) for her help producing and analysing recombinant antibodies, the Institut Pierre-Gilles de Gennes (IPGG) for use of clean room facilities and the laser engraver (CII08, Axyslaser)., ANR-14-CE16-0011,DROP-mAbs,Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques(2014), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-10-EQPX-0034,IPGG,Institut Pierre Gilles de Gennes pour la microfluidique(2010), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Pasteur [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)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Bruhns, Pierre, Appel à projets générique - Analyse en profondeur de répertoires d'anticorps par microfluidique en gouttelettes couplé à du séquençage haut-débit pour le diagnostic et la découverte d'anticorps thérapeutiques - - DROP-mAbs2014 - ANR-14-CE16-0011 - Appel à projets générique - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Equipements d'excellence - Institut Pierre Gilles de Gennes pour la microfluidique - - IPGG2010 - ANR-10-EQPX-0034 - EQPX - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Biomedical Engineering, Somatic hypermutation, Bioengineering, Cancer Vaccines, Applied Microbiology and Biotechnology, Antibodies, Mice, 03 medical and health sciences, 0302 clinical medicine, Antibody Repertoire, Antigen, Animals, Humans, Antigens, 030304 developmental biology, chemistry.chemical_classification, B-Lymphocytes, 0303 health sciences, biology, High-Throughput Nucleotide Sequencing, DNA, Microfluidic Analytical Techniques, Molecular biology, Reverse transcriptase, 3. Good health, Enzyme, chemistry, Immunization, Immunoglobulin G, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Molecular Medicine, Single-Cell Analysis, Antibody, 030217 neurology & neurosurgery, Ex vivo, Biotechnology
Abstract

International audience; Mining the antibody repertoire of plasma cells and plasmablasts could enable the discovery of useful antibodies for therapeutic or research purposes1. We present a method for high-throughput, single-cell screening of IgG-secreting primary cells to characterize antibody binding to soluble and membrane-bound antigens. CelliGO is a droplet microfluidics system that combines high-throughput screening for IgG activity, using fluorescence-based in-droplet single-cell bioassays2, with sequencing of paired antibody V genes, using in-droplet single-cell barcoded reverse transcription. We analyzed IgG repertoire diversity, clonal expansion and somatic hypermutation in cells from mice immunized with a vaccine target, a multifunctional enzyme or a membrane-bound cancer target. Immunization with these antigens yielded 100–1,000 IgG sequences per mouse. We generated 77 recombinant antibodies from the identified sequences and found that 93% recognized the soluble antigen and 14% the membrane antigen. The platform also allowed recovery of ~450–900 IgG sequences from ~2,200 IgG-secreting activated human memory B cells, activated ex vivo, demonstrating its versatility.

Published
2020
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3. 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

4. Author Correction: High-throughput single-cell activity-based screening and sequencing of antibodies using droplet microfluidics

Author

Samantha N. Stewart, Annabelle Gérard, Bingqing Shen, Colin Brenan, Pascaline Mary, Matthieu Delince, Scott McNamara, Klaus Eyer, Guillaume Mottet, Sami Ellouze, Pierre Bruhns, Adam Woolfe, Pablo Canales-Herrerias, Charina Ortega, Antoine Sautel-Caillé, Carlos Castrillon, Raphael Clement Li-Ming Doineau, Jean Baudry, Allan Jensen, Odile Richard-Le Goff, Clément Nizak, Bruno Iannascoli, Vera Menrath, Gregory Rose, Adeline Poitou, Luis Briseño-Roa, Yannick Pousse, Bin Jia, Roshan Kumar, Marcel Reichen, Baptiste Saudemont, Alexei Godina, Patrick England, Kevin Grosselin, Gaël A. Millot, Sosthene Essono, and Andrew D. Griffiths

Subjects
Cell activity, Chemistry, Biomedical Engineering, Molecular Medicine, Bioengineering, Droplet microfluidics, Computational biology, Applied Microbiology and Biotechnology, Throughput (business), Biotechnology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

5. 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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