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1. Targeting cholangiocarcinoma cells by cold piezoelectric plasmas: in vitro efficacy and cellular mechanisms

Author

Manon Soulier, Bouchra Lekbaby, Imane Houari, Henri Decauchy, Allan Pavy, Alexia Coumes, Romain Morichon, Thierry Dufour, and Laura Fouassier

Subjects
Medicine, Science
Abstract

Abstract Cold piezoelectric plasma (CPP) is a novel approach in cancer therapy, enabling the development of portable treatment devices capable of triggering cancer cell death. While its effectiveness remains underexplored, this research focuses on its application against cholangiocarcinoma (CCA), an aggressive cancer of the biliary tract. A CPP device is utilized to generate either a corona discharge (Pz-CD) or a dielectric barrier discharge (Pz-DBD) for in vitro experiments. Notably, Pz-CD can deliver more power than Pz-DBD, although both sources produce significant levels of reactive species in plasma and liquid phases. This work shows that CPP causes a gradient increase in medium temperature from the center towards the edges of the culture well, especially for longer treatment times. Although Pz-CD heats more significantly, it cools quickly after plasma extinction. When applied to human CCA cells, CPP shows immediate and long-term effects, more localized for Pz-CD, while more uniform for Pz-DBD. Immediate effects result also in actin cytoskeleton remodeling without alteration of the cell membrane permeability. Long-term effects of CPP, although the antioxidant system is engaged, include activation of the DNA damage response pathway leading to cell death. In conclusion, CPP should be recognized as a promising antitumor therapy.

Published
2024
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2. Cancer-Associated Fibroblasts and Extracellular Matrix: Therapeutical Strategies for Modulating the Cholangiocarcinoma Microenvironment

Author

Mirko Minini and Laura Fouassier

Subjects
cancer-associated fibroblasts, extracellular matrix, immune-exclusion, tumor microenvironment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

During the last decade, immunotherapy has radically changed perspectives on anti-tumor treatments. However, solid tumor treatment by immunotherapy has not met expectations. Indeed, poor clinical response to treatment has highlighted the need to understand and avoid immunotherapy resistance. Cholangiocarcinoma (CCA) is the second cause of hepatic cancer-related deaths because of drug inefficacy and chemo-resistance in a majority of patients. Thus, intense research is ongoing to better understand the mechanisms involved in the chemo-resistance processes. The tumor microenvironment (TME) may be involved in tumor therapy resistance by limiting drug access. Indeed, cells such as cancer-associated fibroblasts (CAFs) alter TME by producing in excess an aberrant extracellular matrix (ECM). Interestingly, CAFs are the dominant stromal component in CCA that secrete large amounts of stiff ECM. Stiff ECM could contribute to immune exclusion by limiting anti-tumor T-cells drop-in. Herein, we summarize features, functions, and interactions among CAFs, tumor-associated ECM, and immune cells in TME. Moreover, we discuss the strategies targeting CAFs and the remodeling of the ECM to improve immunotherapy and drug therapies.

Published
2023
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3. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Author

Alba Nicolas-Boluda, Javier Vaquero, Lene Vimeux, Thomas Guilbert, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptula, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, José Courty, Laura Fouassier, Florence Gazeau, and Emmanuel Donnadieu

Subjects
tumor, extracellular matrix, T lymphocytes, immunotherapy, cell migration, stiffness, Medicine, Science, Biology (General), QH301-705.5
Abstract

Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

Published
2021
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4. A PDZ-Like Motif in the Biliary Transporter ABCB4 Interacts with the Scaffold Protein EBP50 and Regulates ABCB4 Cell Surface Expression.

Author

Quitterie Venot, Jean-Louis Delaunay, Laura Fouassier, Danièle Delautier, Thomas Falguières, Chantal Housset, Michèle Maurice, and Tounsia Aït-Slimane

Subjects
Medicine, Science
Abstract

ABCB4/MDR3, a member of the ABC superfamily, is an ATP-dependent phosphatidylcholine translocator expressed at the canalicular membrane of hepatocytes. Defects in the ABCB4 gene are associated with rare biliary diseases. It is essential to understand the mechanisms of its canalicular membrane expression in particular for the development of new therapies. The stability of several ABC transporters is regulated through their binding to PDZ (PSD95/DglA/ZO-1) domain-containing proteins. ABCB4 protein ends by the sequence glutamine-asparagine-leucine (QNL), which shows some similarity to PDZ-binding motifs. The aim of our study was to assess the potential role of the QNL motif on the surface expression of ABCB4 and to determine if PDZ domain-containing proteins are involved. We found that truncation of the QNL motif decreased the stability of ABCB4 in HepG2-transfected cells. The deleted mutant ABCB4-ΔQNL also displayed accelerated endocytosis. EBP50, a PDZ protein highly expressed in the liver, strongly colocalized and coimmunoprecipitated with ABCB4, and this interaction required the QNL motif. Down-regulation of EBP50 by siRNA or by expression of an EBP50 dominant-negative mutant caused a significant decrease in the level of ABCB4 protein expression, and in the amount of ABCB4 localized at the canalicular membrane. Interaction of ABCB4 with EBP50 through its PDZ-like motif plays a critical role in the regulation of ABCB4 expression and stability at the canalicular plasma membrane.

Published
2016
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5. Autoimmunity affecting the biliary tract fuels the immunosurveillance of cholangiocarcinoma

Author

Franck Letourneur, Jérémy Augustin, Mark J. Kurth, Julie Le Naour, Sylvie Lachkar, Pamela Caudana, Eliane Piaggio, Youra Kim, Sarah Levesque, Jie S. Zhu, Guido Kroemer, Jonathan Pol, Bouchra Lekbaby, Andrea Checcoli, Patrick S.C. Leung, Allan Sauvat, Shashi Gujar, Agathe Delaune, Chantal Housset, Pierre de la Grange, Paule Opolon, Laura Fouassier, Noémie Robil, Laurence Zitvogel, Patrick Soussan, Juliette Paillet, Céleste Plantureux, Jimena Tosello Boari, M. Eric Gershwin, Isabelle Martins, Maria Chiara Maiuri, Cédric Coulouarn, Gautier Stoll, Norma Bloy, Gwennhael Autret, Juliette Hamroune, 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 de Paris (UP), Institut Gustave Roussy (IGR), Institut Curie [Paris], Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], 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), GenoSplice [Paris], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of California [Los Angeles] (UCLA), University of California, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dalhousie University [Halifax], Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Université Paris-Saclay, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Karolinska University Hospital [Stockholm], Association pour la lutte contre les maladies inflammatoires du foie et des voies biliaires, Dalhousie Medical Research Foundation, Agence National de la Recherche, ERA-Net for Research on Rare Diseases, Association pour la recherche sur le cancer, Cancéropôle Ile-de-France, Chancellerie des universités de Paris, Fondation pour la Recherche Médicale, Elior, European Research Area Network on Cardiovascular Diseases, Gustave Roussy Odyssea, European Union Horizon 2020, Canadian Cancer Society, Project Oncobiome, Fondation Carrefour, GDW20171100085, High-end Foreign Expert Program in China, Institut National du Cancer, Inserm, Institut Universitaire de France, LeDucq Foundation, LabEx, Recherche Hospitalo-Universitaire Torino Lumière, Seerave Foundation, Canadian Institutes of Health Research, Site de Recherche intégrée sur le Cancer Stratified Oncology Cell DNA Repair and Tumor Immune Elimination, Cancer Research and Personalized Medicine, Multi-Organism Institute (ITMO) Aviesan Cancer, Association Française d'Hépatologie, Site de Recherche intégrée sur le Cancer Cancer Research and Personalized Medicine, Ligue contre le Cancer, 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), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
CD4-Positive T-Lymphocytes, Cholangitis, Autoimmunity, CD8-Positive T-Lymphocytes, Inbred C57BL, medicine.disease_cause, Medical and Health Sciences, Malignant transformation, Cholangiocarcinoma, Mice, 0302 clinical medicine, Immunologic, Neoplasms, 2.1 Biological and endogenous factors, Immunology and Allergy, Medicine, Aetiology, Cancer, 0303 health sciences, Tumor, Liver Disease, Forkhead Transcription Factors, 3. Good health, Immunosurveillance, medicine.anatomical_structure, Liver, Biliary tract, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, cardiovascular system, Cytokines, Female, Biotechnology, Liver Cancer, Monitoring, T cell, Chronic Liver Disease and Cirrhosis, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Autoimmune Disease, digestive system, Cell Line, Primary sclerosing cholangitis, Experimental, 03 medical and health sciences, Rare Diseases, Monitoring, Immunologic, Cell Line, Tumor, parasitic diseases, Animals, cardiovascular diseases, Digestive Diseases - (Gallbladder), 030304 developmental biology, business.industry, Neoplasms, Experimental, medicine.disease, digestive system diseases, Mice, Inbred C57BL, Bile Duct Neoplasms, Cancer research, Digestive Diseases, business
Abstract

International audience; Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.

Published
2021
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6. Photothermal Depletion of Cancer-Associated Fibroblasts Normalizes Tumor Stiffness in Desmoplastic Cholangiocarcinoma

Author

Gilles Renault, Gautier Laurent, Emmanuel Donnadieu, Laura Fouassier, Florence Gazeau, Alba Nicolas-Boluda, Rana Bazzi, Javier Vaquero, Stéphane Roux, Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris isabelle.dusanter@inserm.fr., Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateforme Imagerie du petit animal [Institut Cochin], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Debray, Bernard, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Population, General Physics and Astronomy, Metal Nanoparticles, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, medicine.disease_cause, Extracellular matrix, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, Cancer-Associated Fibroblasts, [CHIM] Chemical Sciences, medicine, Tumor Microenvironment, Humans, [CHIM]Chemical Sciences, General Materials Science, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Tumor microenvironment, Chemistry, General Engineering, Cancer, Photothermal therapy, Fibroblasts, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Gold, 0210 nano-technology, Carcinogenesis
Abstract

Physical oncology recognizes tissue stiffness mediated by activation of cancer-associated fibroblasts (CAF) and extracellular matrix remodeling as an active modulator of tumorigenesis, treatment resistance, and clinical outcome. Cholangiocarcinoma (CCA) is a highly aggressive and chemoresistant desmoplastic cancer enriched in CAF. CCA's stroma mechanical properties are considered responsible for its chemoresistant character. To normalize tumor mechanics, we propose a physical strategy based on remotely light-activated nanohyperthermia to modulate the tumor microenvironment. In this study, we report the use of multifunctional iron oxide nanoflowers decorated with gold nanoparticles (GIONF) as efficient nanoheaters to achieve complete tumor regression following three sessions of mild hyperthermia. The preferential uptake of GIONF by CAF allowed targeting this cell population, which resulted in a significant early reduction of tumor stiffness followed by tumor regression. In conclusion, our study highlights a spatially and temporally controlled physical strategy, GIONF-mediated photothermal therapy to deplete CAF and normalize the tumor mechanics that may apply to desmoplastic cancer and CCA treatment.

Published
2020
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7. Intrahepatic cholangiocarcinoma: A single-cell resolution unraveling the complexity of the tumor microenvironment

Author

Luca Fabris, Laura Fouassier, Jesper B. Andersen, Gestionnaire, Hal Sorbonne Université, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Yale School of Medicine [New Haven, Connecticut] (YSM), IT University of Copenhagen (ITU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University Hospital of Padua, Yale University School of Medicine, IT University of Copenhagen, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
[SDV]Life Sciences [q-bio], Cell, Bile Duct Neoplasm, Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine, Tumor Microenvironment, Humans, tumor-stroma interactions, cholangiocytes, Intrahepatic Cholangiocarcinoma, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, cholangiocarcinoma, tumor-stroma interactions, cholangiocytes, Hepatology, Resolution (electron density), [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, Cancer research, 030211 gastroenterology & hepatology, cholangiocarcinoma
Abstract

International audience

Published
2020
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8. Treatment of carcinomas using atmospheric pressure plasma jets: from targets to in vivo models to investigate innocuity and therapeutic efficiency

Author

Florian Judée, Vaquero, J., Laura Fouassier, Thierry Dufour, Laboratoire de Physique des Plasmas (LPP), Université Paris-Saclay-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-École polytechnique (X)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
antitumor effects, APPJ, [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], FOS: Biological sciences, FOS: Physical sciences, Quantitative Biology - Tissues and Organs, Medical Physics (physics.med-ph), Tissues and Organs (q-bio.TO), Carcinomas, Physics - Medical Physics
Abstract

International audience; Atmospheric pressure plasma jets (APPJ) are investigated as an efficient approach to induce antitumor effects of cancerous tissues without inducing any damage (e.g. dessication, burnings). For this, a two-steps methodology has been developed where first APPJ are calibrated and characterized on targets mimicking electrical properties of living organisms (mice, human body) and second where they are applied on murine models to demonstrate their innocuity and therapeutic efficiency.

Published
2019

9. Insulin receptor isoform A favors tumor progression in human hepatocellular carcinoma by increasing stem/progenitor cell features

Author

Dominique Wendum, Olivier Scatton, Marie Lequoy, Christèle Desbois-Mouthon, Olivier Rosmorduc, Laura Fouassier, Fatiha Merabtene, Zeina Salamé, Yves Chrétien, Laetitia Fartoux, Eva Benabou, Françoise Praz, Sylvana Tahraoui, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU), Service de Pathologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Service d'hépatologie [Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité Mixte de Service d'Imagerie et de Cytométrie (UMS LUMIC), Service d'hépatologie [CHU Saint-Antoine], Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Service d'Hépato-gastro-entérologie [CHU Saint-Antoine]

Subjects
0301 basic medicine, Cancer Research, Carcinoma, Hepatocellular, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Invasion, Antigens, CD, Mice, Inbred NOD, Cell Line, Tumor, medicine, Animals, Humans, Protein Isoforms, Progenitor cell, Autocrine signalling, ComputingMilieux_MISCELLANEOUS, Liver Neoplasms, Cell migration, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cytokeratin-19, medicine.disease, Immunohistochemistry, Receptor, Insulin, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, 3. Good health, Insulin receptor, 030104 developmental biology, Oncology, Cell culture, Tumor progression, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Cancer research, biology.protein, Disease Progression, Neoplastic Stem Cells, Heterografts, Female, INSR, Liver cancer
Abstract

International audience; Hepatocellular carcinoma (HCC) is one of the most common and deadly neoplasms. Insulin receptor (IR) exists in two isoforms, IR-A and IR-B, the latter being predominantly expressed in normal adult hepatocytes while IR-A is overexpressed in HCC to the detriment of IR-B. This study evaluated the biological functions associated with IR-A overexpression in HCC in relation to expression of its ligand IGF-II. The value of INSRA:INSRB ratio which was increased in ˜70% of 85 HCC was associated with stem/progenitor cell features such as cytokeratin-19 and α-fetoprotein and correlated with shorter patient survival. IGF2 mRNA upregulation was observed in 9.4% of HCC and was not associated with higher INSRA:INSRB ratios. Ectopic overexpression of IR-A in two HCC cell lines presenting a strong autocrine IGF-II secretion loop or not stimulated cell migration and invasion. In cells cultured as spheroids, IR-A overexpression promoted gene programs related to stemness, inflammation and cell movement. IR-A also increased cell line tumorigenicity in vivo after injection to immunosuppressed mice and the sphere-forming cells made a significant contribution to this effect. Altogether, these results demonstrate that IR-A is a novel player in HCC progression.

Published
2019
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10. IGF2/IR/IGF1R pathway in tumor cells and myofibroblasts mediates resistance to EGFR inhibition in cholangiocarcinoma

Author

Cédric Coulouarn, Audrey Clapéron, Cindy Lobe, Sylvana Tahraoui, Laura Fouassier, Dominique Wendum, Fatiha Merabtene, Christèle Desbois-Mouthon, Chantal Housset, Martine Mergey, Javier Vaquero, Françoise Praz, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie Pathologique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 2011 25574 and 2014 47502, Fondation de France, RS14/75-112), GEFLUC (2013), and ANR (ANR-17-CE14-0013-01, Ligue Contre le Cancer, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE14-0013,EBPatobile,Régulation de l'homéostasie biliaire par la protéine d'échafaudage EBP50(2017), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Centre de Recherche Saint-Antoine ( UMRS893 )

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], growth-factor receptor, Receptor, IGF Type 1, Cholangiocarcinoma, Mice, 0302 clinical medicine, Cancer-Associated Fibroblasts, cetuximab, Epidermal growth factor receptor, Myofibroblasts, biology, Chemistry, gemcitabine, 3. Good health, ErbB Receptors, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, biliary-tract cancer, human hepatocellular-carcinoma, Heterografts, Erlotinib, Tyrosine kinase, Signal Transduction, medicine.drug, Cell signaling, insulin, Stromal cell, epithelial-mesenchymal transition, open-label, phase-2 trial, 03 medical and health sciences, Insulin-Like Growth Factor II, Cancer stem cell, Cell Line, Tumor, medicine, Animals, Humans, Protein Kinase Inhibitors, Cell Proliferation, Insulin-like growth factor 1 receptor, [ SDV ] Life Sciences [q-bio], Growth factor, oxaliplatin, Receptors, Somatomedin, Receptor, Insulin, respiratory tract diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, biology.protein
Abstract

Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition. Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models. Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial–mesenchymal transition (EMT) and a cancer stem cell (CSC)–like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation. Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282–96. ©2018 AACR.

Published
2018
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11. Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Author

Laura Fouassier, Javier Vaquero, Anna Pellat, HAL-UPMC, Gestionnaire, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Receptor, ErbB-4, Receptor, ErbB-3, Receptor, ErbB-2, Bile Duct Diseases, Receptor tyrosine kinase, Cholangiocyte, 03 medical and health sciences, ErbB Receptors, 0302 clinical medicine, ErbB, Tumor Microenvironment, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, ERBB3, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epidermal growth factor receptor, Receptor, skin and connective tissue diseases, Hepatology, biology, Epithelial Cells, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Liver Regeneration, 3. Good health, 030104 developmental biology, Biliary tract, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Bile Ducts, Signal Transduction
Abstract

The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (Hepatology 2018;67:762-773).

Published
2018
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12. Epithelial-mesenchymal transition in cholangiocarcinoma: from clinical evidence to regulatory networks

Author

Laura Fouassier, Thanh Huong Nguyen Ho-Bouldoires, Audrey Clapéron, Valérie Paradis, Nathalie Guedj, Javier Vaquero, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation ARC pour la recherche sur le cancer, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Anatomie Pathologique [CHU Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Cell type, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, medicine, Humans, Epithelial–mesenchymal transition, Transcription factor, Tumor microenvironment, Hepatology, Mesenchymal stem cell, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Prognosis, Epithelial-mesenchymal transition, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Invasiveness, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer cell, embryonic structures, Cancer research, Chemoresistance
Abstract

International audience; Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.

Published
2016
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13. Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Author

Stuart J. Forbes, Guro Elisabeth Lind, Pietro Invernizzi, Rocio I.R. Macias, Eugenio Gaudio, Jesus M. Banales, Kirsten Muri Boberg, Michael Trauner, Marco Marzioni, Diego F. Calvisi, Vincenzo Cardinale, Domenico Alvaro, Chiara Raggi, Antonio Benedetti, Andreas Geier, Javier Vaquero, Luca Maroni, Jose J.G. Marin, Jesper B. Andersen, Joachim C. Mertens, Laura Fouassier, Maria J. Perugorria, Trine Folseraas, and Guido Carpino

Subjects
medicine.medical_specialty, Statement (logic), MEDLINE, information science, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, parasitic diseases, Medicine, cardiovascular diseases, ddc:610, Intensive care medicine, International research, Heterogeneous group, Biliary tract cancer, Hepatology, business.industry, High mortality, fungi, Expert consensus, Late diagnosis, 030220 oncology & carcinogenesis, cardiovascular system, 030211 gastroenterology & hepatology, business
Abstract

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.

Published
2016
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14. Mechanical induction of the tumorigenic b-catenin pathway by tumour growth pressure

Author

Silvia Fre, Sylviane Lesieur, Aude Michel, Colette Rey, Thomas Rio-Frio, Joanne Whitehead, Heldmuth Latorre-Ossa, Hélène Marie, Audrey Clapéron, Gaëlle Béalle, Chantal Housset, Nicolas Servant, Emmanuel Farge, Maria Elena Fernandez-Sanchez, Laura Fouassier, Jean-Luc Gennisson, Mickael Tanter, Sandrine Barbier, Laura Brulle, Sylvie Robine, Christine Ménager, Elodie Girard, Physico-Chimie-Curie (PCC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), PHysicochimie des Electrolytes et Nanosystèmes InterfaciauX (PHENIX), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Institut de Chimie du CNRS (INC), Physique des ondes pour la médecine, 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 National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Langevin - Ondes et Images (UMR7587) (IL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), 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), Next generation sequencing platform [Institut Curie, Paris], Institut Curie [Paris], Physico-chimie, pharmacotechnie, biopharmacie (PCPB), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Génétique et Biologie du Développement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-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), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), and FARGE, Emmanuel

Subjects
Male, Tumour heterogeneity, Carcinogenesis, [SDV]Life Sciences [q-bio], Active Transport, Cell Nucleus, Metal Nanoparticles, Connective tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Biology, medicine.disease_cause, Adherens junction, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Pressure, Tumor Microenvironment, medicine, Animals, Phosphorylation, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, beta Catenin, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, Multidisciplinary, Receptors, Notch, Proto-Oncogene Proteins c-ret, Epithelial Cells, Anatomy, Epithelium, Cell biology, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Catenin, Colonic Neoplasms, Magnets, Female, Signal Transduction, Aberrant crypt foci
Abstract

International audience; The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells 1,2. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithe-lium. In the early stage of mouse colon tumour development in the Notch 1 Apc 1/1638N mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and b-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesench-ymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of b-catenin on Tyr654, imparing its interaction with the E-cadherin in adhe-rens junctions, and which was followed by b-catenin nuclear trans-location after 15 days. As a consequence, increased expression of b-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic b-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity. To test the tumorous impact of early tumour growth pressure on non-tumorous epithelial tissues in vivo, apart from the mechanical stiffness characteristic of the microenvironment of late tumours 1-6

Published
2015
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15. E-cadherin, guardian of liver physiology

Author

Nicolas Chignard, Laura Fouassier, Javier Vaquero, Ester Gonzalez-Sanchez, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Administateur, HAL Sorbonne Université

Subjects
Male, Pathology, medicine.medical_specialty, Carcinogenesis, Cholangitis, Sclerosing, Inflammation, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Medicine, Animals, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, Hepatology, business.industry, Cadherin, Liver Neoplasms, Gastroenterology, Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Biological Sciences, medicine.disease, Cadherins, Epithelium, Pathophysiology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, medicine.symptom, business, Liver cancer
Abstract

The precise roles of E-cadherin in the liver and liver carcinogenesis are still unknown. Here we show that mice lacking E-cadherin in the liver develop spontaneous periportal inflammation via an impaired intrahepatic biliary network, as well as periductal fibrosis, which resembles primary sclerosing cholangitis. Inducible gene knockout studies identified E-cadherin loss in biliary epithelial cells as a causal factor of cholangitis induction, and dysregulated E-cadherin expression was also seen in patients with primary sclerosing cholangitis. E-cadherin loss also significantly accelerates genetically and chemically engineered liver cancer through epithelial–mesenchymal transition, up-regulation of stem cell markers, and ERK activation. Thus, E-cadherin plays critical roles in maintaining homeostasis and suppressing carcinogenesis in the liver.

Published
2014
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16. Altered hepatobiliary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation

Author

Nicolas Chignard, Véronique Barbu, Laura Fouassier, Emmanuel Jacquemin, Christine Demeilliers, Noureddine Lomri, Martine Mergey, François Paye, Chantal Housset, Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de chirurgie générale et digestive [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Male, medicine.medical_specialty, Liver cytology, Cystic Fibrosis Transmembrane Conductance Regulator, Down-Regulation, Cholestasis, Intrahepatic, Biology, Cholesterol 7 alpha-hydroxylase, 03 medical and health sciences, 0302 clinical medicine, Cholestasis, Downregulation and upregulation, Biliary atresia, Internal medicine, medicine, Humans, Cells, Cultured, 030304 developmental biology, Regulation of gene expression, Adenosine Triphosphatases, 0303 health sciences, Hepatology, Bile duct, Gallbladder, Infant, Epithelial Cells, medicine.disease, medicine.anatomical_structure, Endocrinology, Gene Expression Regulation, Liver, Child, Preschool, 030211 gastroenterology & hepatology, Female, Bile Ducts, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Recent reports in patients with PFIC1 have indicated that a gene defect in ATP8B1 could cause deregulations in bile salt transporters through decreased expression and/or activity of FXR. This study aimed to: (1) define ATP8B1 expression in human hepatobiliary cell types, and (2) determine whether ATP8B1 defect affects gene expressions related to bile secretion in these cells. ATP8B1 expression was detected by RT-PCR in hepatocytes and cholangiocytes isolated from normal human liver and gallbladder. ATP8B1 mRNA levels were 20- and 200-fold higher in bile duct and gallbladder epithelial cells, respectively, than in hepatocytes. RT-PCR analyses of the liver from two patients with PFIC1, one with PFIC2, one with biliary atresia, showed that, compared to normal liver, hepatic expressions of FXR, SHP, CYP7A1, ASBT were decreased at least by 90% in all cholestatic disorders. In contrast, NTCP transcripts were less decreased (by < or = 30% vs. 97%) in PFIC1 as compared with other cholestatic disorders, while BSEP transcripts, in agreement with BSEP immunohistochemical signals, were normal or less decreased (by 50% vs. 97%). CFTR hepatic expression was decreased (by 80%), exclusively in PFIC1, while bile duct mass was not reduced, as ascertained by cytokeratin-19 immunolabeling. In Mz-ChA-2 human biliary epithelial cells, a significant decrease in CFTR expression was associated with ATP8B1 invalidation by siRNA. In conclusion, cholangiocytes are a major site ofATP8B1 hepatobiliary expression. A defect of ATP8B1 along with CFTR downregulation can impair the contribution of these cells to bile secretion, and potentially explain the extrahepatic cystic fibrosis-like manifestations that occur in PFIC1.

Published
2006
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17. Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic

Author

Laura Fouassier, Maria Guido, Mario Strazzabosco, Enrico Gringeri, Jesus M. Banales, Jose J.G. Marín, Massimiliano Cadamuro, Samantha Sarcognato, Alberto Lasagni, Angela Lamarca, Luca Fabris, and Umberto Cillo

Subjects
0301 basic medicine, Disease, Bioinformatics, oncogenic drivers, Article, Extrahepatic Cholangiocarcinoma, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, extrahepatic cholangiocarcinoma, Tumor Microenvironment, Medicine, molecularly targeted therapies, Humans, Pharmacology (medical), Molecular Targeted Therapy, Precision Medicine, Pharmacology, business.industry, General Medicine, Precision medicine, cholangiocarcinoma, Cholangiocyte, epithelial-to-mesenchymal transition, immunotherapy, tumor microenvironment, Prognosis, 3. Good health, 030104 developmental biology, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Immunotherapy, business, Systematic search
Abstract

INTRODUCTION. Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unravelling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, “Mesenchymal”, “Proliferation”, “Immune”, and “Metabolic”. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified. AREAS COVERED. We offer insights on perturbed pathways, molecular profiling and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA. EXPERT OPINION. eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.

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18. Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease

Author

Amine Majdi, Bruno Fève, Gilles Courtois, Tawhidul Islam, Tatiana Ledent, Tounsia Aït-Slimane, Taïeb Mestiri, Olivier Scatton, Florine Ballenghien, Jean-Louis Delaunay, Fabienne Foufelle, Laura Fouassier, Marta B. Afonso, Carina Prip-Buus, Marthe Moldes, Filomena Conti, Chantal Housset, Marie Lagouge, Axelle Cadoret, Cecília M. P. Rodrigues, Lynda Aoudjehane, Jérémie Gautheron, Vlad Ratziu, Laboratoire de Biologie Cellulaire, UPRES 1833, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Trafic Membranaire et Signalisation Dans les Cellules Epitheliales, Centre de Mathématiques Laurent Schwartz (CMLS), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie, Diabétologie et d'Endocrinologie de la Reproduction [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), CHU Saint-Antoine [APHP]-Centre de Recherche Saint-Antoine (CR Saint-Antoine), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Male, Necroptosis, Diet, High-Fat, Gene Knockout Techniques, Mice, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, medicine, Animals, Humans, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Mice, Knockout, Liver injury, Acrylamides, Sulfonamides, 0303 health sciences, Hepatology, business.industry, Fatty liver, nutritional and metabolic diseases, Middle Aged, medicine.disease, digestive system diseases, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Treatment Outcome, Mitochondrial respiratory chain, Liver, Receptor-Interacting Protein Serine-Threonine Kinases, 030220 oncology & carcinogenesis, Hepatocytes, Cancer research, Female, Steatosis, Steatohepatitis, business, Protein Kinases, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MLKL, NAFLD, NASH, RIPK1, Signal Transduction
Abstract

Background & Aims In non-alcoholic fatty liver disease (NAFLD), hepatocytes can undergo necroptosis: a regulated form of necrotic cell death mediated by the receptor-interacting protein kinase (RIPK) 1. Herein, we assessed the potential for RIPK1 and its downstream effector mixed lineage kinase domain-like protein (MLKL) to act as therapeutic targets and markers of activity in NAFLD. Methods C57/BL6J-mice were fed a normal chow diet or a high-fat diet (HFD). The effect of RIPA-56, a highly specific inhibitor of RIPK1, was evaluated in HFD-fed mice and in primary human steatotic hepatocytes. RIPK1 and MLKL concentrations were measured in the serum of patients with NAFLD. Results When used as either a prophylactic or curative treatment for HFD-fed mice, RIPA-56 caused a downregulation of MLKL and a reduction of liver injury, inflammation and fibrosis, characteristic of non-alcoholic steatohepatitis (NASH), as well as of steatosis. This latter effect was reproduced by treating primary human steatotic hepatocytes with RIPA-56 or necrosulfonamide, a specific inhibitor of human MLKL, and by knockout (KO) of Mlkl in fat-loaded AML-12 mouse hepatocytes. Mlkl-KO led to activation of mitochondrial respiration and an increase in β-oxidation in steatotic hepatocytes. Along with decreased MLKL activation, Ripk3-KO mice exhibited increased activities of the liver mitochondrial respiratory chain complexes in experimental NASH. In patients with NAFLD, serum concentrations of RIPK1 and MLKL increased in correlation with activity. Conclusion The inhibition of RIPK1 improves NASH features in HFD-fed mice and reverses steatosis via an MLKL-dependent mechanism that, at least partly, involves an increase in mitochondrial respiration. RIPK1 and MLKL are potential serum markers of activity and promising therapeutic targets in NAFLD. Lay summary There are currently no pharmacological treatment options for non-alcoholic fatty liver disease (NAFLD), which is now the most frequent liver disease. Necroptosis is a regulated process of cell death that can occur in hepatocytes during NAFLD. Herein, we show that RIPK1, a gatekeeper of the necroptosis pathway that is activated in NAFLD, can be inhibited by RIPA-56 to reduce not only liver injury, inflammation and fibrosis, but also steatosis in experimental models. These results highlight the potential of RIPK1 as a therapeutic target in NAFLD.

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19. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Author

Alba Nicolas-Boluda, Javier Vaquero, Lene Vimeux, Thomas Guilbert, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptula, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, José Courty, Laura Fouassier, Florence Gazeau, Emmanuel Donnadieu, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Matière et Systèmes Complexes (MSC (UMR_7057)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Bellvitge Biomedical Research Institute IDIBELL [Barcelona, Spain], Laboratoire de Physique des Plasmas (LPP), Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École polytechnique (X)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Medical University of Białystok (MUB), Institute of Physics, Polish Academy of Sciences, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Courty, José, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CNRS UMR 7057 - Laboratoire Matières et Systèmes Complexes (MSC) (MSC), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Medical University of Bialystok [Bialystok, Pologne], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
tumor, Mouse, cell migration, QH301-705.5, T-Lymphocytes, extracellular matrix, Science, Programmed Cell Death 1 Receptor, T lymphocytes, Immunoteràpia, T cells, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Physiological Phenomena, Protein-Lysine 6-Oxidase, Mice, stiffness, Cell Movement, Tumor Microenvironment, Animals, Biology (General), Càncer, Immune Checkpoint Inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Cancer Biology, Cancer, Neoplasms, Experimental, Mice, Inbred C57BL, Cèl·lules T, Medicine, Female, Collagen, immunotherapy, Immunotherapy, Research Article
Abstract

International audience; Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

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20. Self‐Assemblies of Fe 3 O 4 Nanocrystals: Toward Nanoscale Precision of Photothermal Effects in the Tumor Microenvironment

Author

Laura Fouassier, Florence Gazeau, Alba Nicolas-Boluda, Zhijie Yang, Thomas Guilbert, Florent Carn, Marie-Paule Pileni, Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Shandong University, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)

Subjects
Tumor microenvironment, Materials science, Nanotechnology, 02 engineering and technology, Photothermal therapy, 010402 general chemistry, 021001 nanoscience & nanotechnology, Condensed Matter Physics, 01 natural sciences, 0104 chemical sciences, Electronic, Optical and Magnetic Materials, Biomaterials, Nanocrystal, Electrochemistry, [CHIM]Chemical Sciences, 0210 nano-technology, Nanoscopic scale
Abstract

International audience; Fe3O4 nanocrystals are self‐assembled into two different conformations: colloidosome and supraball that confer them with distinct properties determining their photo‐induced heating capacities. These self‐assemblies are assessed for photothermal therapy, an adjuvant strategy for tumor therapy. The tumor microenvironment is a heterogeneous ecosystem including immune cells and the extracellular matrix. The interactions between photothermal therapy agents and the different components of the tumor microenvironment determine the outcome of this therapy. In this study, the fate of both colloidosomes and supraballs within the tumor microenvironment in comparison to their Fe3O4 nanocrystal building blocks is revealed. This study highlights how these two hybrid self‐assemblies target different compartments of the tumor microenvironment and trigger local photothermal damages that are inaccessible for isolated nanocrystals and not predicted by global temperature measurements.

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