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1. Monitoring HSP70 exosomes in cancer patients’ follow up: a clinical prospective pilot study

Author

Gaëtan Chanteloup, Marine Cordonnier, Nicolas Isambert, Aurélie Bertaut, Alice Hervieu, Audrey Hennequin, Maxime Luu, Sylvie Zanetta, Bruno Coudert, Leila Bengrine, Isabelle Desmoulins, Laure Favier, Aurélie Lagrange, Pierre-Benoit Pages, Ivan Gutierrez, Jeanine Lherminier, Laure Avoscan, Clémentine Jankowski, Cédric Rébé, Angélique Chevriaux, Marie-Martine Padeano, Charles Coutant, Sylvain Ladoire, Sylvain Causeret, Laurent Arnould, Céline Charon-Barra, Vanessa Cottet, Julie Blanc, Christine Binquet, Marc Bardou, Carmen Garrido, and Jessica Gobbo

Subjects
exosomes, hsp70, diagnosis, liquid biopsy, cancer, Cytology, QH573-671
Abstract

Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.

Published
2020
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2. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients

Author

Marine Cordonnier, Charlée Nardin, Gaëtan Chanteloup, Valentin Derangere, Marie-Paule Algros, Laurent Arnould, Carmen Garrido, François Aubin, and Jessica Gobbo

Subjects
melanoma, exosome, pd-l1/pd-1, immune checkpoint, follow-up, Cytology, QH573-671
Abstract

In the era of immunotherapies there is an urgent need to implement the use of circulating biomarkers in clinical practice to facilitate personalized therapy and to predict treatment response. We conducted a prospective study to evaluate the usefulness of circulating exosomal-PD-L1 in melanoma patients’ follow-up. We studied the dynamics of exosomal-PD-L1 from 100 melanoma patients by using an enzyme-linked immunosorbent assay. We found that PD-L1 was secreted through exosomes by melanoma cells. Exosomes carrying PD-L1 had immunosuppressive properties since they were as efficient as the cancer cell from which they derive at inhibiting T-cell activation. In plasma from melanoma patients, the level of PD-L1 (n= 30, median 64.26 pg/mL) was significantly higher in exosomes compared to soluble PD-L1 (n= 30, 0.1 pg/mL). Furthermore, exosomal-PD-L1 was detected in all patients whereas only 67% of tumour biopsies were PD-L1 positive. Although baseline exosomal-PD-L1 levels were not associated with clinic-pathologic characteristics, their variations after the cures (ΔExoPD-L1) correlated with the tumour response to treatment. A ΔExoPD-L1 cut-off of> 100 was defined, yielding an 83% sensitivity, a 70% specificity, a 91% positive predictive value and 54% negative predictive values for disease progression. The use of the cut-off allowed stratification in two groups of patients statistically different concerning overall survival and progression-free survival. PD-L1 levels in circulating exosomes seem to be a more reliable marker than PD-L1 expression in tumour biopsies. Monitoring of circulating exosomal-PD-L1 may be useful to predict the tumour response to treatment and clinical outcome.

Published
2020
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3. Membrane-bound exosomal HSP70 as a biomarker for detection and monitoring of malignant solid tumours: a pilot study

Author

Marine Cordonnier, Gaëtan Chanteloup, Carmen Garrido, Nicolas Isambert, Guillaume Marcion, Jessica Gobbo, and Aurélie Bertaut

Subjects
Endosome, Medicine (miscellaneous), HSP70-exosomes, Study Protocol, 03 medical and health sciences, 0302 clinical medicine, microRNA, medicine, Liquid biopsy, Survival rate, 030304 developmental biology, Pilot study, Solid tumours, 0303 health sciences, lcsh:R5-920, Cancer diagnosis and monitoring, business.industry, Cancer, medicine.disease, Microvesicles, 3. Good health, Biomarker (cell), 030220 oncology & carcinogenesis, Cancer cell, Cancer research, business, lcsh:Medicine (General)
Abstract

Background Cancer is the second leading cause of death globally. Early detection and disease management lead to a better survival rate. Consequently, discovery of novel methods in cancer early diagnosis is a field of active research. Minimally invasive liquid biopsies are generating growing interest. Circulating tumour cells (CTCs) have been identified in patients’ blood; nevertheless, these cells are rare and heterogeneous. Exosomes are extracellular nanovesicles released into the extracellular environment via the endosomal vesicle pathway and found in different body fluids. Exosomes deliver bioactive cargo such as proteins, mRNA and miRNA to recipient cells in the tumour environment. We have recently shown that heat shock protein 70 (HSP70) is detected in the membrane of tumour-derived exosomes, in contrast to normal cells. One single cancer cell can release thousands of HSP70-exosomes, facilitating detection. The aim of the pilot study ExoDiag is to determine whether it is possible to detect and quantify HSP70-exosomes in blood in patients with solid cancers. Methods Bicentric pilot study that will include 60 adult patients with metastatic and non-metastatic solid tumours and 20 healthy volunteers. Exosomes will be isolated from blood and urine samples, and HSP70 concentration will be determined. Patients will be followed for 1 year. The study is sponsored by Georges-François Leclerc Centre and is currently ongoing. Discussion We expect to demonstrate that HSP70-exosomes could be a powerful tool to diagnose cancer and to guide clinicians in therapeutic decision-making, improving patient’s care. Trial Registration ClinicalTrials.gov identifier NCT02662621. Registered 20 January 2016, https://clinicaltrials.gov/ct2/show/study/NCT02662621?term=NCT02662621&rank=1

Published
2020
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4. Exosomal HSP70 for Monitoring of Frontotemporal Dementia and Alzheimer’s Disease: Clinical and FDG-PET Correlation

Author

Vanesa Pytel, María Nieves Cabrera-Martín, Carmen Garrido, Teresa Moreno-Ramos, Marine Cordonnier, Jessica Gobbo, Gaëtan Chanteloup, Jordi A. Matías-Guiu, Ulises Gómez-Pinedo, and Jorge Matías-Guiu

Subjects
Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Disease, Neuropsychological Tests, Exosomes, Correlation, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Fluorodeoxyglucose F18, Internal medicine, mental disorders, medicine, Humans, HSP70 Heat-Shock Proteins, Correlation of Data, Aged, business.industry, General Neuroscience, Neurodegeneration, General Medicine, medicine.disease, Microvesicles, Hsp70, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Frontotemporal Dementia, Positron-Emission Tomography, Cohort, Female, Radiopharmaceuticals, Geriatrics and Gerontology, business, Biomarkers, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract

We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Published
2019
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5. Increased Levels of Interleukin-17A Exosomes in Psoriasis

Author

Jessica Gobbo, Charlée Nardin, Gaëtan Chanteloup, Laura Boullerot, Claire Jacquin-Porretaz, Olivier Adotevi, François Aubin, Carmen Garrido, Marine Cordonnier, and Valentin Vautrot

Subjects
0301 basic medicine, Adult, Male, il-17, Adolescent, exosomes, Dermatology, Exosome, Severity of Illness Index, Flow cytometry, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immune system, Psoriasis, Medicine, Humans, Prospective Studies, Aged, 030203 arthritis & rheumatology, Aged, 80 and over, medicine.diagnostic_test, business.industry, Interleukin-17, Interleukin, General Medicine, psoriasis, Middle Aged, medicine.disease, Microvesicles, Up-Regulation, Blot, 030104 developmental biology, RL1-803, Immunology, Female, Interleukin 17, business, Biomarkers
Abstract

Exosomes are involved in modulating the immune system and mediating communication between cells. The aim of this study was to investigate the involvement of exosomes in psoriasis. Exosomes from patients with psoriasis were analysed by nanoparticle tracking analysis and protein expression was analysed by western blotting. The concentration of HSP70 was determined by an enzyme-linked immunosorbent assay, and concentrations of interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-17A and tumour necrosis factor alpha (TNF-α) were determined by flow cytometry. Based on the severity of psoriasis, evaluated by body surface area (≤ 10% vs. > 10%), 2 groups of patients were compared (49 with mild psoriasis and 71 with moderate-to-severe psoriasis). The number (2.52×1011 ± 2.29×1010 vs. 1.79×1011 ± 1.93×1010, p = 0.19) and size (94.44 ± 22.00 nm vs. 96.87 ± 28.30 nm, p = 0.72) of exosomes and the concentration of HSP70 in the exosomes were not significantly different in the 2 groups of patients. IL-17A exosome levels were significantly higher in patients with moderate-to-severe psoriasis compared with those with mild psoriasis (p = 0.02). There were no significant differences in levels of TNF-α, IL-1, IL-2, IL-6 and IL-10. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis. These data confirm the involvement of circulating exosomes in psoriasis, in particular in moderate-to-severe psoriasis, through IL-17A-producing exosomes.

Published
2019

6. Tracking the evolution of circulating exosomal-PD-L1 to monitor melanoma patients

Author

F. Aubin, Marine Cordonnier, Carmen Garrido, Jessica Gobbo, Valentin Derangère, Charlée Nardin, Gaëtan Chanteloup, M.-P. Algros, and Laurent Arnould

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Histology, Exosome, 03 medical and health sciences, 0302 clinical medicine, PD-L1, Internal medicine, PD-L1/PD-1, medicine, follow-up, exosome, lcsh:QH573-671, Prospective cohort study, Melanoma, immune checkpoint, biology, lcsh:Cytology, business.industry, Cell Biology, medicine.disease, Microvesicles, Immune checkpoint, 3. Good health, Circulating biomarkers, 030104 developmental biology, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, business, Research Article
Abstract

In the era of immunotherapies there is an urgent need to implement the use of circulating biomarkers in clinical practice to facilitate personalized therapy and to predict treatment response. We conducted a prospective study to evaluate the usefulness of circulating exosomal-PD-L1 in melanoma patients’ follow-up. We studied the dynamics of exosomal-PD-L1 from 100 melanoma patients by using an enzyme-linked immunosorbent assay. We found that PD-L1 was secreted through exosomes by melanoma cells. Exosomes carrying PD-L1 had immunosuppressive properties since they were as efficient as the cancer cell from which they derive at inhibiting T-cell activation. In plasma from melanoma patients, the level of PD-L1 (n= 30, median 64.26 pg/mL) was significantly higher in exosomes compared to soluble PD-L1 (n= 30, 0.1 pg/mL). Furthermore, exosomal-PD-L1 was detected in all patients whereas only 67% of tumour biopsies were PD-L1 positive. Although baseline exosomal-PD-L1 levels were not associated with clinic-pathologic characteristics, their variations after the cures (ΔExoPD-L1) correlated with the tumour response to treatment. A ΔExoPD-L1 cut-off of> 100 was defined, yielding an 83% sensitivity, a 70% specificity, a 91% positive predictive value and 54% negative predictive values for disease progression. The use of the cut-off allowed stratification in two groups of patients statistically different concerning overall survival and progression-free survival. PD-L1 levels in circulating exosomes seem to be a more reliable marker than PD-L1 expression in tumour biopsies. Monitoring of circulating exosomal-PD-L1 may be useful to predict the tumour response to treatment and clinical outcome.

Published
2020

7. Exosomal miRNA: Small Molecules, Big Impact in Colorectal Cancer

Author

Jessica Gobbo, Carmen Garrido, Mohammed I. Y. Elmallah, Gaëtan Chanteloup, Marine Cordonnier, François Aubin, and Valentin Vautrot

Subjects
0303 health sciences, Tumor microenvironment, Stromal cell, Colorectal cancer, Angiogenesis, business.industry, Context (language use), Review Article, medicine.disease, Non-coding RNA, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Microvesicles, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, microRNA, medicine, Cancer research, business, 030304 developmental biology
Abstract

Colorectal cancer (CRC) is one of the major causes of cancer-related deaths worldwide. Tumor microenvironment (TME) contains many cell types including stromal cells, immune cells, and endothelial cells. The TME modulation explains the heterogeneity of response to therapy observed in patients. In this context, exosomes are emerging as major contributors in cancer biology. Indeed, exosomes are implicated in tumor proliferation, angiogenesis, invasion, and premetastatic niche formation. They contain bioactive molecules such as proteins, lipids, and RNAs. More recently, many studies on exosomes have focused on miRNAs, small noncoding RNA molecules able to influence protein expression. In this review, we describe miRNAs transported by exosomes in the context of CRC and discuss their influence on TME and their potential as circulating biomarkers. This overview underlines emerging roles for exosomal miRNAs in cancer research for the near future.

Published
2019

8. Membrane-anchored heat-shock protein 70 (Hsp70) in cancer

Author

Carmen Garrido, Marine Cordonnier, Valentin Vautrot, Mohammed I. Y. Elmallah, Jessica Gobbo, Gaëtan Chanteloup, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Cancer Research, Carcinogenesis, Cell Survival, Hsp70 translocation, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Exosomes, Targeting Hsp70, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Heat shock protein, Neoplasms, Extracellular, Humans, HSP70 Heat-Shock Proteins, Exosomal Hsp70, biology, Chemistry, Cell Membrane, Hsp70, Cell biology, Up-Regulation, [SDV] Life Sciences [q-bio], 030104 developmental biology, Membrane, Membrane Hsp70, Oncology, 030220 oncology & carcinogenesis, Chaperone (protein), Cancer cell, biology.protein, Disease Progression, Protein folding
Abstract

International audience; Hsp70 is a highly conserved and inducible heat shock protein that belongs to the HSP70 family of molecular chaperones and plays a central role in protein homeostasis. The main function of Hsp70 is to protect cells from physiological, pathological and environmental insults, as it assists an ATP-dependent manner the process of protein folding. Since Hsp70 provides critical cell survival functions, cancer cells are assumed to rely on this chaperone. Strong evidence suggests that Hsp70 is upregulated in different type of cancers and is involved in tumor growth, invasion, migration and resistance to anti-cancer therapy. Interestingly, this Hsp70 upregulation induces Hsp70 re-location into plasma membrane. In this review, the role of Hsp70 in cancer will be discussed focusing particularly on the extracellular membrane-bound Hsp70. The mechanism by which Hsp70 is translocated to plasma membrane of tumor cells and the recent discoveries of drugs targeting this Hsp70 in cancer therapy will be also highlighted.

Published
2019
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9. HSP110 translocates to the nucleus upon genotoxic chemotherapy and promotes DNA repair in colorectal cancer cells

Author

Jérôme Paggetti, Burhan Uyanik, Oleg N. Demidov, Alexandre M.M. Dias, Laurence Dubrez, Carmen Garrido, Gaëtan Chanteloup, Sebastien Causse, Baptiste Dumetier, Etienne Moussay, Guillaume Marcion, Christophe Boudesco, Jessica Gobbo, Lucile Dondaine, Aurélie de Thonel, Bogdan B. Grigorash, Gustavo J. Gozzi, Céline Mirjolet, Romain Douhard, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Luxembourg Institute of Health (LIH), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
0301 basic medicine, Cancer Research, Ku80, DNA End-Joining Repair, DNA damage, DNA repair, Colorectal cancer, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Biology, medicine.disease_cause, Translocation, Genetic, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Mice, Inbred NOD, Cell Line, Tumor, Genetics, medicine, Animals, Humans, DNA Breaks, Double-Stranded, HSP110 Heat-Shock Proteins, Molecular Biology, Ku Autoantigen, ComputingMilieux_MISCELLANEOUS, Cell Nucleus, Ku70, Mutation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, HCT116 Cells, 3. Good health, Oxaliplatin, DNA-Binding Proteins, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Cancer research, Colorectal Neoplasms, DNA, medicine.drug, DNA Damage, Mutagens
Abstract

International audience; A multicenter clinical study demonstrated the presence of a loss-of-function HSP110 mutation in about 15% of colorectal cancers, which resulted from an alternative splicing and was produced at the detriment of wild-type HSP110. Patients expressing low levels of wild-type HSP110 had excellent outcomes (i.e. response to an oxaliplatin-based chemotherapy). Here, we show in vitro, in vivo, and in patients' biopsies that HSP110 co-localizes with DNA damage (γ-H2AX). In colorectal cancer cells, HSP110 translocates into the nucleus upon treatment with genotoxic chemotherapy such as oxaliplatin. Furthermore, we show that HSP110 interacts with the Ku70/Ku80 heterodimer, an essential element of the non-homologous end joining (NHEJ) repair machinery. We also demonstrate by evaluating the resolved 53BP1 foci that depletion in HSP110 impairs repair steps of the NHEJ pathway, which is associated with an increase in DNA double-strand breaks and in the cells' sensitivity to oxaliplatin. HSP110-depleted cells sensitization to oxaliplatin-induced DNA damage is abolished upon re-expression of HSP110. Confirming a role for HSP110 in DNA non-homologous repair, SCR7 and NU7026, two inhibitors of the NHEJ pathway, circumvents HSP110-induced resistance to chemotherapy. In conclusion, HSP110 through its interaction with the Ku70/80 heterodimer may participate in DNA repair, thereby inducing a protection against genotoxic therapy.

Published
2019
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10. PD-L1 dans les exosomes circulants de patients atteints de mélanome : un nouveau biomarqueur ?

Author

Jessica Gobbo, Valentin Derangère, Guillaume Marcion, Carmen Garrido, L. Arnould, Marine Cordonnier, Gaëtan Chanteloup, Charlée Nardin, F. Aubin, and M.-P. Algros

Subjects
Dermatology
Abstract

Le pronostic des patients atteints de melanome avance s’est considerablement ameliore depuis l’avenement des therapies ciblees et des immunotherapies. Cependant, tous les patients ne beneficient pas de ces traitements (tts) a cause de resistances primaires ou acquises. Il apparait donc indispensable de developper des biomarqueurs permettant de selectionner les patients potentiellement repondeurs aux tts, d’evaluer precocement l’efficacite de ces tts et diagnostiquer precocement la recidive de la maladie. Nous avons evalue l’interet du dosage de PD-L1 dans les exosomes circulants de patients atteints de melanome avance. Cent patients suivis entre novembre 2016 et janvier 2019 etaient inclus. Les exosomes etaient isoles par ultracentrifugations. L’expression de PD-L1 dans les exosomes circulants (Exo-PD-L1) etait mesuree en Elisa (PD-L1 Human ELISA Kit, Invitrogen) et comparee a l’expression de PDL1 dans le plasma et dans la tumeur (immunohistochimie). Dans un premier temps, nous avons demontre la presence de PD-L1 dans les exosomes de lignees cellulaires de melanome (B16F10, SK-MEL-2). Les Exo-PD-L1 etaient capables d’inhiber in vitro l’activite des lymphocytes T suggerant leur role immunosuppresseur. Chez les patients, le taux median d’Exo-PD-L1 etait de 64,26 pg/mL, significativement plus eleve que le taux de PD-L1 retrouve dans le plasma (0,1 pg/ml). Exo-PD-L1 etait identifie chez tous les patients alors que le marquage PD-L1 tumoral n’etait present que chez 67 % des patients. La valeur initiale d’Exo-PD-L1 n’etait pas correlee aux caracteristiques clinico-histologiques ni au volume tumoral. Cependant, les variations de taux d’Exo-PD-L1 (ΔExo-PD-L1) etaient correlees a la reponse au traitement et a la survie des patients (n = 46). Une augmentation du taux d’Exo-PD-L1 superieure a 100 pg/ml etait predictive d’une progression de la maladie avec une sensibilite de 83 %, specificite de 70 %, valeur predictive positive de 91 % et valeur predictive negative de 54 %. L’utilisation de ce cut-off (augmentation ≥ 100 pg/ml) permettait de stratifier les patients en 2 groupes distincts de survie sans progression et survie globale (p = 0,011 et 0,048). Au total, le taux d’Exo-PD-L1 semble etre un biomarqueur de suivi de la maladie plus facilement identifiable que le taux plasmatique de PD-L1. Le role d’Exo-PD-L1 dans l’immunosurveillance au cours du melanome a recemment ete rapporte ainsi que dans les cancers ORL. Nos resultats suggerent que la variation du taux d’Exo-PD-L1 pourrait etre un biomarqueur de reponse au traitement et un marqueur pronostique independant chez les patients atteints de melanome avance. Des etudes complementaires sont necessaires pour confirmer l’interet de ce marqueur en pratique clinique.

Published
2020
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11. HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis

Author

Isabelle Plo, Marine Cordonnier, Martin E. Gleave, Lucia Kubovcakova, Aurélie de Thonel, Selim Ramla, Jean Noel Bastie, Paul Sagot, François Girodon, Valérie Mezger, Jean-Luc Villeval, Marie-Lorraine Chretien, Franck Vitte, Laurent Martin, Matthieu Mosca, Fernando Rodrigues-Lima, Margaux Sevin, Sylvain Audia, Gaëtan Chanteloup, Nicolas Pernet, Carmen Garrido, Radek C. Skoda, Catherine Lacout, Sebastien Causse, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biomédecine et hématologie expérimentale (hôpital universitaire de Basel), Hôpital universitaire de Basel, Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Cypath (Dijon), Cypath, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Unité 'Biologie Fonctionnelle et Adaptative' / Equipe 'Réponses Moléculaires et Cellulaires aux Xénobiotiques', Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Maternité, Obstétrique et Gynécologie, CHU Dijon, University of British Columbia (UBC), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Hématologie, Physiologie de la Nutrition et Toxicologie (NUTox) (U866, Lipides et nutrition, équipe 7) (NUTox), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), université de Bourgogne, LNC, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Ligue Nationnale Contre le Cancer, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], HSP27 Heat-Shock Proteins, Oligonucleotides, General Physics and Astronomy, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], urologic and male genital diseases, Idiopathic pulmonary fibrosis, Mice, 0302 clinical medicine, Megakaryocyte, Fibrosis, Transduction, Genetic, hemic and lymphatic diseases, Leukocytes, STAT5 Transcription Factor, Molecular Targeted Therapy, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Bone Marrow Transplantation, Multidisciplinary, biology, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], medicine.anatomical_structure, Thrombopoietin, 030220 oncology & carcinogenesis, embryonic structures, Female, Whole-Body Irradiation, endocrine system, animal structures, Science, Bone Marrow Cells, Mice, Transgenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Hsp27, [SDV.CAN] Life Sciences [q-bio]/Cancer, Heat shock protein, Cell Line, Tumor, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, Myelofibrosis, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Janus Kinase 2, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, Primary Myelofibrosis, Mutation, Cancer research, biology.protein, lcsh:Q, business, K562 Cells
Abstract

Heat shock protein 27 (HSP27/HSPB1) is a stress-inducible chaperone that facilitates cancer development by its proliferative and anti-apoptotic functions. The OGX-427 antisense oligonucleotide against HSP27 has been reported to be beneficial against idiopathic pulmonary fibrosis. Here we show that OGX-427 is effective in two murine models of thrombopoietin- and JAKV617F-induced myelofibrosis. OGX-427 limits disease progression and is associated with a reduction in spleen weight, in megakaryocyte expansion and, for the JAKV617F model, in fibrosis. HSP27 regulates the proliferation of JAK2V617F-positive cells and interacts directly with JAK2/STAT5. We also show that its expression is increased in both CD34+ circulating progenitors and in the serum of patients with JAK2-dependent myeloproliferative neoplasms with fibrosis. Our data suggest that HSP27 plays a key role in the pathophysiology of myelofibrosis and represents a new potential therapeutic target for patients with myeloproliferative neoplasms., Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease

Published
2018
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12. Suivi du taux de PD-L1 dans les exosomes pour évaluer la réponse tumorale dans le mélanome

Author

Gaëtan Chanteloup, Guillaume Marcion, M.-P. Algros, Marine Cordonnier, Valentin Derangère, L. Arnould, Jessica Gobbo, Carmen Garrido, Charlée Nardin, and F. Aubin

Subjects
Dermatology
Abstract

Introduction Le pronostic des patients atteints de melanome avance s’est considerablement ameliore depuis l’avenement des therapies ciblees et des immunotherapies. Cependant, tous les patients ne beneficient pas de ces traitements a cause de resistances primaires ou acquises. Il apparait donc indispensable de developper des biomarqueurs permettant de selectionner les patients potentiellement repondeurs et permettant de surveiller l’efficacite des traitements. Nous avons evalue l’interet du dosage de PD-L1 dans les exosomes circulants de patients atteints de melanome avance. Materiel et methodes Cent patients suivis entre novembre 2016 et janvier 2019 etaient inclus. Les exosomes etaient isoles par ultracentrifugation. L’expression PD-L1 dans les exosomes circulants (Exo-PD-L1) etait mesuree en Elisa (PD-L1 Human ELISA Kit, Invitrogen) et compare a l’expression PDL1 tumoral et dans le plasma. Resultats Dans un premier temps, nous avons montre la detection des Exo-PD-L1 dans des lignees cellulaires de melanome (B16F10, SK-MEL-2). Les Exo-PD-L1 etaient capables d’inhiber in vitro l’activite des lymphocytes T suggerant leur role immunosuppresseur. Chez les patients, le taux median des ExoPD-L1 etait de 64,26 pg/mL, significativement plus eleve que les taux a peine detectable de PD-L1 dans le plasma (0,1 pg/ml). De plus, les Exo-PD-L1 etait trouves chez tous les patients alors que le marquage PD-L1 tumoral n’etait present que chez 67 % des patients. La valeur initiale des Exo-PD-L1 n’etait pas correlee aux caracteristiques clinico-histologiques ni au volume tumoral. Cependant, les variations des taux des Exo-PD-L1 (ΔExo-PD-L1) etaient correlees a la reponse au traitement et a la survie des patients (n = 46). Une variation du taux des Exo-PD-L1superieure a 100 pg/ml etait predictive d’une progression de la maladie avec une sensibilite de 83 % et specificite de 70 %, une VPN de 91 % et une VPN de 54 %. L’utilisation de ce cut-off (variation de 100 pg/ml) permettait de stratifier les patients en 2 groupes distincts de survie sans progression et survie globale (p = 0,011 et 0,048). Discussion Au total, le taux des Exo-PD-L1 semble etre un biomarqueur de suivi de la maladie plus facilement identifiable que le taux plasmatique de PD-L1. Le role des exo-PD-L1 dans l’immunosurveillance au cours du melanome a recemment ete rapporte (Chen et al., 2018) ainsi que dans les cancers ORL et certains cancers non a petites cellules du poumon (Theodoraki et al. 2018 and Xie et al., 2018). Conclusion Nos resultats suggerent que la variation du taux des exo-PD-L1 pourrait etre un biomarqueur de reponse au traitement et un marqueur pronostique independant chez les patients atteints de melanome avance. Des etudes complementaires sont necessaires pour confirmer le role et l’usage de ce marqueur en pratique clinique.

Published
2019
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13. Visualization of RNA-Quadruplexes in Live Cells

Author

Pascale Winckler, Judy M. Y. Wong, Fares Katranji, Jean-Marie Perrier-Cornet, Marc Pirrotta, Aurélien Laguerre, Gaëtan Chanteloup, David Monchaud, Kyle R. Hukezalie, Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Faculty of Pharmaceutical Sciences, University of British Columbia, University of British Columbia (UBC), Conception, synthèse et vectorisation de biomolécules. (CSVB), Institut Curie-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, and Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]

Subjects
Static Electricity, Melanoma, Experimental, Ligands, 010402 general chemistry, G-quadruplex, 01 natural sciences, Biochemistry, Catalysis, Mice, 03 medical and health sciences, chemistry.chemical_compound, Colloid and Surface Chemistry, Biomimetics, Cations, Cell Line, Tumor, Fluorescence Resonance Energy Transfer, Animals, Humans, [CHIM]Chemical Sciences, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, heterocyclic compounds, ComputingMilieux_MISCELLANEOUS, Chelating Agents, Fluorescent Dyes, 030304 developmental biology, Photons, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, biology, Chemistry, RNA, DNA, General Chemistry, Fluorescence, Molecular biology, 3. Good health, 0104 chemical sciences, Cell biology, Visualization, G-Quadruplexes, Förster resonance energy transfer, Microscopy, Fluorescence, Cell culture, MCF-7 Cells, biology.protein, Antibody
Abstract

Visualization of DNA and RNA quadruplex formation in human cells was demonstrated recently with different quadruplex-specific antibodies. Despite the significant interest in these immunodetection approaches, dynamic detection of quadruplex in live cells remains elusive. Here, we report on NaphthoTASQ (N-TASQ), a next-generation quadruplex ligand that acts as a multiphoton turn-on fluorescent probe. Single-step incubation of human and mouse cells with N-TASQ enables the direct detection of RNA-quadruplexes in untreated cells (no fixation, permeabilization or mounting steps), thus offering a unique, unbiased visualization of quadruplexes in live cells.

Published
2015
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14. Exosomes in cancer theranostic: Diamonds in the rough

Author

Renaud Seigneuric, Jessica Gobbo, Carmen Garrido, Pierre Fumoleau, Marine Cordonnier, Gaëtan Chanteloup, Nicolas Isambert, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer ( LabEx LipSTIC ), Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Université Paris-Sud - Paris 11 ( UP11 ) -École pratique des hautes études ( EPHE ) -Institut Gustave Roussy ( IGR ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Université de Franche-Comté ( UFC ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
0301 basic medicine, Endosome, Review, exosomes, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Models, Biological, Theranostic Nanomedicine, Metastasis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Drug Delivery Systems, Neoplasms, Heat shock protein, cancer diagnosis, Biomarkers, Tumor, medicine, Animals, Humans, Tumor microenvironment, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, Cancer, Cell Biology, medicine.disease, Primary tumor, Microvesicles, 3. Good health, Cell biology, 030104 developmental biology, Tumor progression, heat shock proteins, cancer therapy
Abstract

IF 3.306; International audience; During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSP-exosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.

Published
2017
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15. 521 Circulating PD-L1-exosomes to monitor tumor response in melanoma patients

Author

Valentin Derangère, Carmen Garrido, Marine Cordonnier, Marie Paule Algros, Gaëtan Chanteloup, L. Arnould, F. Aubin, Jessica Gobbo, and Charlée Nardin

Subjects
biology, business.industry, Melanoma, Cell Biology, Dermatology, medicine.disease, Tumor response, Biochemistry, Microvesicles, PD-L1, biology.protein, Cancer research, Medicine, business, Molecular Biology
Published
2019
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16. Circulating PD-L1-exosomes to monitor tumor response in melanoma patients

Author

Jessica Gobbo, Gaëtan Chanteloup, Marie Paule Algros, Marine Cordonnier, Guillaume Marcion, Valentin Derangère, François Aubin, Charlée Nardin, Carmen Garrido, and Laurent Arnould

Subjects
Cancer Research, biology, business.industry, Melanoma, medicine.disease, Tumor response, Microvesicles, 03 medical and health sciences, Circulating biomarkers, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, PD-L1, medicine, Cancer research, biology.protein, business, 030215 immunology
Abstract

9517 Background: In the era of effective molecular targeted treatments and immunotherapies, there is an urgent need to implement the use of circulating biomarkers in the clinic to facilitate personalized therapy and predict treatment response. We conducted a retrospective study to demonstrate the involvement of circulating PD-L1 exosomes in melanoma patients. Methods: One hundred melanoma patients were included. Exosomes were isolated by ultracentrifugation and evaluated by nanoparticle tracking analysis using a NS300 Instrument (Nanosight, Amesbury, UK). Isolated exosomes were tested for the expression of exosomes markers such as TSG101. PD-L1 expression in plasma and in melanoma plasma-derived exosomes (ExoPD-L1) was measured using an enzyme-linked immunosorbent assay (PD-L1 Human ELISA Kit, Invitrogen). Results: First, ExoPD-L1 was assessed in melanoma cell lines. Exosomes may have a role in cancer immunosuppression mediated by T-cells since they were as efficient as cancer cells to inhibit T-cells activation. In melanoma patients, ExoPD-L1 (median 64,26 pg/mL) was significantly higher than free PD-L1 in the plasma which was barely detectable (0,1 pg/mL). Furthermore, ExoPD-L1 was detected in all patients whereas only 67 % were PD-L1 positive in tumor. Although baseline ExoPD-L1 levels were not associated with clinicopathologic characteristics and tumour burden, ExoPD-L1 variations (ΔExoPD-L1) after treatment correlated with tumor response and survival. A ΔExoPD-L1 cut-off of > 100 was defined, yielding a 83% sensitivity, a 70% specificity, a 91% positive predictive value and a 54% negative predictive values for disease progression. The use of this cut-off allowed stratification in two groups of patients statistically different in terms of overall survival and progression free survival. Conclusions: PD-L1 level in circulating exosomes may be a more reliable marker than PD-L1 expression in the tumor tissue. Monitoring of circulating exosomal PD-L1 may be a promising biomarker to predict tumor response and correlate with survival.

Published
2019
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17. Membrane-bound exosomal HSP70 as a biomarker for detection and monitoring of malignant solid tumours: a pilot study

Author

Gaétan Chanteloup, Marine Cordonnier, Nicolas Isambert, Aurélie Bertaut, Guillaume Marcion, Carmen Garrido, and Jessica Gobbo

Subjects
Pilot study, Liquid biopsy, HSP70-exosomes, Solid tumours, Cancer diagnosis and monitoring, Medicine (General), R5-920
Abstract

Abstract Background Cancer is the second leading cause of death globally. Early detection and disease management lead to a better survival rate. Consequently, discovery of novel methods in cancer early diagnosis is a field of active research. Minimally invasive liquid biopsies are generating growing interest. Circulating tumour cells (CTCs) have been identified in patients’ blood; nevertheless, these cells are rare and heterogeneous. Exosomes are extracellular nanovesicles released into the extracellular environment via the endosomal vesicle pathway and found in different body fluids. Exosomes deliver bioactive cargo such as proteins, mRNA and miRNA to recipient cells in the tumour environment. We have recently shown that heat shock protein 70 (HSP70) is detected in the membrane of tumour-derived exosomes, in contrast to normal cells. One single cancer cell can release thousands of HSP70-exosomes, facilitating detection. The aim of the pilot study ExoDiag is to determine whether it is possible to detect and quantify HSP70-exosomes in blood in patients with solid cancers. Methods Bicentric pilot study that will include 60 adult patients with metastatic and non-metastatic solid tumours and 20 healthy volunteers. Exosomes will be isolated from blood and urine samples, and HSP70 concentration will be determined. Patients will be followed for 1 year. The study is sponsored by Georges-François Leclerc Centre and is currently ongoing. Discussion We expect to demonstrate that HSP70-exosomes could be a powerful tool to diagnose cancer and to guide clinicians in therapeutic decision-making, improving patient’s care. Trial Registration ClinicalTrials.gov identifier NCT02662621 . Registered 20 January 2016, https://clinicaltrials.gov/ct2/show/study/NCT02662621?term=NCT02662621&rank=1

Published
2020
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18. Increased Levels of Interleukin-17A Exosomes in Psoriasis

Author

Claire Jacquin-Porretaz, Marine Cordonnier, Charlée Nardin, Laura Boullerot, Gaetan Chanteloup, Valentin Vautrot, Olivier Adotevi, Carmen Garrido, Jessica Gobbo, and François Aubin

Subjects
exosomes, psoriasis, il-17, Dermatology, RL1-803
Abstract

Exosomes are involved in modulating the immune system and mediating communication between cells. The aim of this study was to investigate the involvement of exosomes in psoriasis. Exosomes from patients with psoriasis were analysed by nanoparticle tracking analysis and protein expression was analysed by western blotting. The concentration of HSP70 was determined by an enzyme-linked immunosorbent assay, and concentrations of interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-17A and tumour necrosis factor alpha (TNF-α) were determined by flow cytometry. Based on the severity of psoriasis, evaluated by body surface area (≤ 10% vs. > 10%), 2 groups of patients were compared (49 with mild psoriasis and 71 with moderate-to-severe psoriasis). The number (2.52×1011 ± 2.29×1010 vs. 1.79×1011 ± 1.93×1010, p = 0.19) and size (94.44 ± 22.00 nm vs. 96.87 ± 28.30 nm, p = 0.72) of exosomes and the concentration of HSP70 in the exosomes were not significantly different in the 2 groups of patients. IL-17A exosome levels were significantly higher in patients with moderate-to-severe psoriasis compared with those with mild psoriasis (p = 0.02). There were no significant differences in levels of TNF-α, IL-1, IL-2, IL-6 and IL-10. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis. These data confirm the involvement of circulating exosomes in psoriasis, in particular in moderate-to-severe psoriasis, through IL-17A-producing exosomes.

Published
2019
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19. HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis

Author

Margaux Sevin, Lucia Kubovcakova, Nicolas Pernet, Sébastien Causse, Franck Vitte, Jean Luc Villeval, Catherine Lacout, Marine Cordonnier, Fernando Rodrigues-Lima, Gaétan Chanteloup, Matthieu Mosca, Marie-Lorraine Chrétien, Jean Noël Bastie, Sylvain Audia, Paul Sagot, Selim Ramla, Laurent Martin, Martin Gleave, Valérie Mezger, Radek Skoda, Isabelle Plo, Carmen Garrido, François Girodon, and Aurélie de Thonel

Subjects
Science
Abstract

Myelofibrosis is a chronic degenerative disorder characterized by progressive bone marrow fibrosis. Here, the authors show that the chaperone HSP27 contributes to myelofibrosis via regulation of the JAK2/STAT5 pathway, and that antisense oligonucleotides targeting HSP27 are effective in two mouse models of the disease

Published
2018
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