Development of new diagnostic and prognostic tools and new therapeutic approaches
In the field of cancer treatment research, immunotherapies are booming, in particular the use of T lymphocytes expressing chimeric antigen receptors (CAR-T). The team led by Emmanuel Donnadieu has improved the understanding of the main negative and positive regulations of anti-tumor immune cells that apply directly to CAR T cells. In particular, the team has shown that T lymphocytes can be blocked in their anti-tumor activities and identified a detrimental impact of the extracellular matrix and macrophages on the development of tumors (1).
The team led by Julie Helft studies the myeloid phagocytic cells that regulate anti-tumor responses and develops therapeutic tools to target them and improve the response to immunotherapies by blocking immune checkpoints (2).
The team led by Sandrine Bourdoulous has identified a mechanism that inhibits the ERBB2/HER2 oncogene responsible for 25% of breast cancers. The team develops new diagnostic and prognostic biomarkers for HER2-positive breast cancers as well as innovative therapeutic approaches to fight against mechanisms of resistance to current therapies.
The group led by Armelle Prévost (team Anne Hosmalin, Rémi Cheynier) studies the immunoregulatory role of two enzymes likely to constitute new therapeutic targets for melanoma: inducible nitric oxide synthetase (NOS2) and IL-4 Induced gene 1 (IL4I1), which might be involved in the escape of melanoma from immune surveillance.
The work of the team led by Jérome Bertherat on pituitary, thyroid and adrenal endocrine tumors aims to establish their molecular classification, making it possible to develop diagnostic tools and to highlight abnormalities in target signaling pathways for new approaches of treatment (3).
The team led by Éric Pasmant seeks to better understand the genetic mechanisms explaining rare tumor predisposition syndromes, in the context of neurofibromatosis (NF) types 1 and 2, schwannomatosis and digestive tumor predisposition syndromes. It 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 and the search for therapeutic approaches (4).
Metabolism and signaling abnormalities and their pharmacological targeting
The team led by Béatrice Romagnolo is currently studying various elements influencing intestinal homeostasis and the development of intestinal tumors: stem cells, nutritional factors, the intestinal microbiota and the immune system. The team recently characterized a new role of Axin 1 in protection against colon cancers, mediated by the immune system (5).
The group led by Mark Scott and Hervé Enslen (Stéfano Marullo team) studies the molecular mechanisms that control important fundamental cellular processes such as proliferation, migration and 3D cellular architecture, and how these can go wrong in different cancers. He is particularly interested in the impact of tumor suppressors (PTEN and p53) and oncoproteins (Mdm2, FAK) on these cellular processes.
The team led by Frédéric Bouillaud is studying the links between cell energy metabolism and cancer. The group of Renaud Dentin and Clotilde Alves-Guerra is interested in the development of colon and liver tumors. They are studying the impact of energy metabolism and oxidative stress on cell proliferation and resistance to cell death, determining factors for the cellular processes involved in tumorigenesis (6).
In the Sélim Aractingi team, Dany Nassar is carrying out a genetic study on 40 cases of skin carcinomas not induced by UV rays, which should allow functional work to characterize their main molecular pathways. Giant congenital nevi are at risk for melanoma. Sarah Guégan demonstrated the presence of original nevi stem cells. She seeks to identify therapeutic targets to reduce tumor mass and the risk of malignant transformation.
The human T-lymphotropic virus type 1 (HTLV-1) is responsible for a form of leukemia due to an uncontrolled proliferation of CD4+ T lymphocytes. The team led by Claudine Pique seeks to understand how HTLV-1 manipulates the host cell to persist within the organism and in some cases, induce the transformation program leading to the development of leukemia.
Immune microenvironment of tumors
The team led by Bruno Lucas is interested in the molecular and cellular actors hindering or improving anti-tumor T immune responses, and the mechanisms involved. Cédric Auffray's group studies in particular the role played by Foxp3+ regulatory T lymphocytes, in suppression of anti-tumor responses. Bruno Martin's group is studying the role of iron as an adjuvant in anti-tumor responses.
Molly Ingersoll's team seeks to characterize the immune microenvironment of the bladder in the context of bladder cancer, in order to improve the immunotherapies developed against this disease.
Stem cells, microenvironment and development of various hematopoietic cancers
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. The team studies splicing and translation abnormalities, which appear as disease initiating mechanisms in preleukemic myelodysplastic syndromes, as well as chemotherapy resistance mechanisms involving signaling, autophagy and ferroptosis abnormalities in acute myeloid leukemia (7).
The team led by Diana Passaro is interested in the tissue microenvironment of hematopoietic stem cells and the mechanisms that regulate multicellular interactions in the bone marrow in the leukemic context. She explores the alterations of these multicellular interactions during acute myeloid and lymphoid leukemias in order to better understand the differences between these diseases and to identify new specific targets.
Genetic instability, regulations of gene expression
Several 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:
The team led by Julie Chaumeil studies the functional role of the conformation and 3D organization of the genome, in the regulation of gene expression during hematopoiesis and during malignant transformations (leukaemia, lymphoma). A recent collaborative study with Drs C Lobry (Saint-Louis Research Institute, Paris) and T Mercher (IGR, Villejuif) has made it possible to characterize oncogenic “Super enhancers” involved in the development of acute megakaryoblastic leukemia (8).
Chromosomal instability, a hallmark of most cancers, is often caused by defects in genome replication. The team led by Benoit Miotto is developing new tests and tools to identify the pathways and signals that impact DNA replication mechanisms (9).
The team led by Bernard Lopez is interested in various stresses (radiation, chemical contaminants, free radicals) that damage DNA, as well as in the subtle balances orchestrating DNA repair and allowing protection against genetic instability. The team recently showed that RAD51 (key protein for homologous recombination) protects against mutagenic repair of DNA double-strand breaks (10).
These basic and translational research programs are based on strong interactions with the medical, surgical and biology departments involved in the care of patients with endocrine tumors, blood diseases, digestive, pulmonary or skin cancers, or sarcomas in the "groupe hospitalo-universitaire AP-HP.Centre - Université Paris Cité", and with the Faculties of Medicine and Health of Université Paris Cité. Institut Cochin also works closely with the Unité de Recherche Clinique des hôpitaux Paris centre and the Centre de Recherche Biologique of Cochin Hospital. The teams are supported by investment programs such as the CARPEM integrated cancer research site (SIRIC), the « Who Am I» et «GR-Ex » LabEx, and by European research networks (H2020, COST actions).
Selected publications in 2022
- Espie D, Donnadieu E. New insights into CAR T cell-mediated killing of tumor cells. Front Immunol. 2022 Sep 15;13:1016208. doi: 10.3389/fimmu.2022.1016208. PMID: 36189315.
- Nalio Ramos R, Missolo-Koussou Y, Gerber-Ferder Y, Bromley C, Bugatti M, Gonzalo Núñez N, Boari Tosello J, Richer W, Denizeau J, Sedlik C, Caudana P, Kotsias F, Niborski LL, Viel S, Bohec M, Lameiras S, Baulande S, Lesage L, Nicolas A, Meseure D, Vincent-Salomon A, Reyal F, Dutertre C-H, Ginhoux F, Vimeux L, Donnadieu E, Buttard B, Galon J, Zelenay S, Vermi W, Guermonprez P, Piaggio E and Helft J. Tissue-resident FOLR2+ macrophages associate with CD8+ T cells infiltration in human breast cancer. Cell. 2022, March 31;185, 1-19. https://doi.org/10.1016/j.cell.2022.02.021
- Jouinot A, Lippert J, Sibony M, Violon F, Jeanpierre L, De Murat D, Armignacco R, Septier A, Perlemoine K, Letourneur F, Izac B, Ragazzon B, Leroy K, Pasmant E, North MO, Gaujoux S, Dousset B, Groussin L, Libe R, Terris B, Fassnacht M, Ronchi CL, Bertherat J, Assie G. Transcriptome in paraffin samples for the diagnosis and prognosis of adrenocortical carcinoma. Eur J Endocrinol. 2022 Apr 21;186(6):607-617. doi: 10.1530/EJE-21-1228. PMID: 35266879
- Rousseau B, Bieche I, Pasmant E, Hamzaoui N, Leulliot N, Michon L, de Reynies A, Attignon V, Foote MB, Masliah-Planchon J, Svrcek M, Cohen R, Simmet V, Augereau P, Malka D, Hollebecque A, Pouessel D, Gomez-Roca C, Guimbaud R, Bruyas A, Guillet M, Grob JJ, Duluc M, Cousin S, de la Fouchardiere C, Flechon A, Rolland F, Hiret S, Saada-Bouzid E, Bouche O, Andre T, Pannier D, El Hajbi F, Oudard S, Tournigand C, Soria JC, Champiat S, Gerber DG, Stephens D, Lamendola-Essel MF, Maron SB, Diplas BH, Argiles G, Krishnan AR, Tabone-Eglinger S, Ferrari A, Segal NH, Cercek A, Hoog-Labouret N, Legrand F, Simon C, Lamrani-Ghaouti A, Diaz LA, Saintigny P, Chevret S, Marabelle A. PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon. Cancer Discov. 2022 Jun 2;12(6):1435-1448.
- Sanson R, Lazzara SL, Cune D, Pitasi CL, Trentesaux C, Fraudeau M, Letourneur F, Saintpierre B, Le Gall M, Bossard P, Terris B, Finetti P, Bertucci F, Mamessier E, Romagnolo B, Perret C. Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect. Cell Mol Gastroenterol Hepatol. 2022 Nov 8;15(3):689-715. doi: 10.1016/j.jcmgh.2022.10.017. PMID: 36356835.
- Sancerni T, Renoult O, Luby A, Caradeuc C, Lenoir V, Croyal M, Ransy C, Aguilar E, Postic C, Bertho G, Dentin R, Prip-Buus C, Pecqueur C, Alves-Guerra MC. UCP2 silencing restrains leukemia cell proliferation through glutamine metabolic remodeling. Front Immunol. 2022 Oct 6;13:960226.
- Decroocq J, Birsen R, Montersino C, Chaskar P, Mano J, Poulain L, Friedrich C, Alary AS, Guermouche H, Sahal A, Fouquet G, Gotanègre M, Simonetta F, Mouche S, Gestraud P, Lescure A, Del Nery E, Bosc C, Grenier A, Mazed F, Mondesir J, Chapuis N, Ho L, Boughalem A, Lelorc'h M, Gobeaux C, Fontenay M, Recher C, Vey N, Guillé A, Birnbaum D, Hermine O, Radford-Weiss I, Tsantoulis P, Collette Y, Castellano R, Sarry JE, Pasmant E, Bouscary D, Kosmider O, Tamburini J. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia. Leukemia. 2022 May;36(5):1237-1252. doi: 10.1038/s41375-022-01541-0. Epub 2022 Mar 30. PMID: 35354920; PMCID: PMC9061298.
- Benbarche S, Lopez CK, Salataj E, Aid Z, Thirant C, Laiguillon MC, Lecourt S, Belloucif Y, Vaganay C, Antonini M, Hu J, da Silva Babinet A, Ndiaye-Lobry D, Pardieu B, Petit A, Puissant A, Chaumeil J, Mercher T, Lobry C. Screening of ETO2-GLIS2-induced Super Enhancers identifies targetable cooperative dependencies in acute megakaryoblastic leukemia. Sci Adv. 2022 Feb 11;8(6):eabg9455. doi: 10.1126/sciadv.abg9455. PMID: 35138899
- Watzky M, Huard S, Juricek L, Dairou J, Chauvet C, Coumoul X, Letessier A, Miotto B. Hexokinase 2 is a transcriptional target and a positive modulator of AHR signalling. Nucleic Acids Res. 2022 Jun 10;50(10):5545-5564. doi: 10.1093/nar/gkac360. PMID: 35609998.
- So A, Dardillac E, Muhammad A, Chailleux C, Sesma-Sanz L, Ragu S, Le Cam E, Canitrot Y, Masson JY, Dupaigne P, Lopez BS, Guirouilh-Barbat J, RAD51 protects against nonconservative DNA double-strand break repair through a nonenzymatic function, Nucleic Acids Res, Volume 50, Issue 5, 21 March 2022, Pages 2651–2666, https://doi.org/10.1093/nar/gkac073