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    Research at Institut Cochin in the field of cancer

    Institut Cochin actively participates in  cancer research, one of its strong axes.

     

    The projects in the field of cancer range from basic research which aims to better understand the molecular and cellular mechanisms that lead to the development of tumors, to translational research in partnership with several hospital departments of the Paris Centre-APHP hospitals.

     

    Several research teams are studying the regulations of gene expression, genome stability and chromatin structure, in order to better understand the consequences of their dysfunction on the development of cancers:

    Defects in DNA replication lead to genomic instability and may lead to diseases including cancer. The team directed by Benoit Miotto develops new assays and tools to identify the pathways and cues that impact on DNA replication mechanisms to unveil key events leading to cancer.

    Gene instability can be caused by various stresses (radiation, chemical contaminants, free radicals, etc.) that damage DNA. The team led by Bernard Lopez is interested in these stresses and the subtle balances orchestrating DNA repair, helping to protect against gene instability.

    The team directed by Julie Chaumeil investigates the functional role of 3D genome conformation, chromatin and nuclear organization in the regulation of gene expression during hematopoiesis and malignant transformation (leukemia / lymphomes).

     

    Viruses are associated with cancers. Human T-lymphotropic virus type 1 (HTLV-1) is thus responsible for a form of leukemia, which corresponds to an uncontrolled proliferation CD4+ T lymphocytes. The team led by Claudine Pique seeks to understand how HTLV-1 manipulates the host cell to persist in the body and in some cases, to induce the transformation program leading to the leukemia development.

    The group led by Mark Scott (Stefano Marullo team) studies the molecular mechanisms that control important fundamental cellular processes such as proliferation, migration and 3D cell architecture, and how these may go awry in different cancer contexts. They have a particular focus on how tumour suppressors (PTEN and p53) and oncoproteins (Mdm2, FAK) impact these cellular processes.

    Sepsis and cancer share pathophysiological similarities, and result from the host's inability to control either tissue invasion by a pathogen or cell transformation. The group led by Frédéric Pène (Chiche, Burgel team) is studying the links between these two pathologies as well as the profound immune alterations that accompany them.

    The team led by Bruno Lucas is interested in the molecular and cellular actors that hinder or improve anti-tumor immune responses and in deciphering the mechanisms involved. They are thus studying the modulation of the effector functions of helper and cytotoxic T lymphocytes throughout tumor development by focusing in particular on the role played by a subpopulation of T lymphocytes specialized in the suppression of immune responses, called regulatory T cells and characterized by their expression of the Foxp3 transcription factor.

     

    Several teams are studying the mechanisms of stem cell dysfunctions that lead to the development of various cancers:

    Colorectal cancer is one of the most common cancers in the world with high mortality. Intestinal stem cells have been shown to be the site of malignant transformation in colorectal cancer. The team led by Béatrice Romagnolo has shown that autophagy plays an essential role in colorectal cancer and in the homeostasis of intestinal stem cells. Their projects aim to elucidate the impact of autophagy on the fate of intestinal stem cells and on the intrinsic characteristics of tumor cells and their microenvironment.

    The team led by Michaela Fontenay and Didier Bouscary is interested in the mechanisms of post-transcriptional regulation of gene expression involved in the biology of normal and leukemic hematopoietic stem cells: a new role for RNA-binding proteins. This team studies splicing and translation abnormalities, which appear as disease-initiating mechanisms in preleukemic myelodysplastic syndromes, as well as chemotherapy resistance mechanisms involving signaling abnormalities, autophagy and ferroptosis in acute myeloid leukemias.

    The team led by Diana Passaro is interested in the environment of hematopoietic stem cells and in the mechanisms that regulate multicellular interactions in the bone marrow, in the leukemic setting. This team explores the alterations of these multicellular interactions during acute myeloid and lymphoid leukemia in order to improve knowledge on the differences between these diseases and to identify new specific targets.

     

    The search for new diagnostic, prognostic tools, and of therapeutic approaches, is a strong focus of Institut Cochin:

    The team led by Sandrine Bourdoulous has identified a mechanism to inhibit the ERBB2/HER2 oncogene, responsible for 25% of breast cancers. This team is developing new diagnostic and prognostic biomarkers for HER2-positive breast cancer as well as innovative therapeutic approaches to fight against the mechanisms of resistance to current therapies.

    In the field of cancer treatment research, immunotherapies are promising. The objective of the team led by Emmanuel Donnadieu is to address questions related to the fields of cancer immunology and cancer immunotherapy. The team aims at characterizing negative and positive regulators of anti-tumoral immune effector cells to improve current cancer treatments.

    The group led by Armelle Prévost (Team Anne Hosmalin, Rémi Cheynier) is studying the immunoregulatory role of two enzymes that may constitute new therapeutic targets for melanoma: inducible nitric oxide synthetase (NOS2) and IL-4 Induced gene 1 (IL4I1), involved in the metabolism of arginine and phenylalanine, respectively. This project is based on recent data suggesting a role of these enzymes in the escape of melanoma from immune surveillance.

    The mechanisms of non-UV-induced skin carcinomas are not known. Dany Nassar (Selim Aractingi team) has collected a series of 40 cases of this type of tumor and is carrying out a genetic study of these specimens which should allow to characterize their main molecular pathways. Giant congenital nevus are at risk for melanoma. Sarah Guégan demonstrated the presence of original nevic stem cells. She seeks to identify therapeutic targets to reduce tumor mass and the risk of malignant transformation.

    The work of the team led by Jérome Bertherat on endocrine pituitary, thyroid and adrenal tumors has made it possible to establish their molecular classification, to develop tools for molecular diagnosis and to highlight abnormalities in the signaling pathways which open up new avenues of treatment.

    The team led by Éric Pasmant tries to better understand the genetic mechanisms explaining rare tumor predisposition syndromes, including types 1 and 2 neurofibromatosis (NF), schwannomatosis and syndromes predisposing to digestive tumors. The team carries out a functional study of tumors associated with NF1 or involving the NF1 gene, for the characterization of the major players in their development to search for new therapeutic approaches.

    The groups of Renaud Dentin and M-Clotilde Alves-Guerra (Frédéric Bouillaud team) are interested in two proteins, UCP2 (uncoupling protein 2) and ChREBP, involved respectively in the development of colon and liver tumors. They study the impact of energy metabolism and oxidative stress on cell proliferation and resistance to cell death, determining factors for cellular processes involved in tumorigenesis, with the perspective of identifying new targets and / or strategies for cancer treatments.

     

    Most of these research projects are carried out within the framework of close collaborations between clinicians from APHP.Centre hospitals and researchers from Institut Cochin, with the objectives to better understand cancer as close as possible to the patient and accelerating the discovery of new diagnostic, prognostic and therapeutic tools. Several teams from the institute participate in SIRIC (Integrated Cancer Research Site) CARPEM (Cancer Research for PErsonalized Medicine) programs. Institut Cochin also works closely with the « Unité de Recherche Clinique des hôpitaux Paris centre » and the « Centre de Recherche Biologique » of Cochin hospital.

    These partnerships with the hospitals are one of the strengths of Institut Cochin and promote a translational research of excellence.

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