Intitulé du sujet: DNA Damage Response/ STING signaling implication during liver tumorigenesis
Sujet
Codirection: non
Nombre de mois: 48 mois
Ecole Doctorale: ED 562 - Bio Sorbonne Paris Cité
Unité de recherche et équipe:
CENTRE DE RECHERCHE DES CORDELIERS U1138
UNIVERSITE PARIS CITE
Coordonnées de l’équipe:
Chantal Desdouets Team: "Genomic Instability, Metabolism, Immunity and Liver Tumorigenesis"
https://www.crcordeliers.fr/en/equipes/proliferation-stress-and-liver-physiopathology-2/
15 rue de l'école de médecine
75006 PARIS
Secteur: Sciences de la vie / Life Sciences
Langue attendue: Anglais
Niveau de langue attendu: C2
Description
Description du sujet:
Hepatocellular carcinoma (HCC) is a highly malignant liver disease responsible for over 700,000 deaths annually. Despite significant advancements in eradicating certain factors leading to its development, the epidemic of Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a new therapeutic challenge. Over the past decade, large-scale genomic/epigenomic/histopathological/immunological studies in a wide variety of tumors have substantially improved the discovery of new cancer drivers. Two main cluster have been defined: the proliferation (Cluster A) and non-proliferation (Cluster B). Frequent activation of classical cell proliferation pathways, frequent TP53 mutations, high chromosomal instability, poor differentiated are hallmarks of Cluster A. Cluster B are related to well differentiated, less aggressive tumors; this cluster being mainly related to CTNNB1 mutations with a chromosomal stability feature. Diagnosis of HCC is unfortunately most often made at advanced stages that are not amenable to potentially curative therapies such as surgery of ablation. Nowadays, it is still fundamental to elucidate the molecular mechanisms leading to HCC progression and improve diagnosis and therapeutic treatments. Our recent findings indicate therapeutic potential in targeting DNA Damage Response (DDR) pathways in HCC. Although DDR was long thought to mainly regulate genome integrity and cell fates, accumulating evidence indicates that genomic instability also triggers inflammatory response, through the cGAS-STING pathway. This DNA sensor plays a dichotomic role in tumorigenesis. Indeed, several studies have demonstrated that the cGAS-STING pathway is activated by DNA damage in antitumor immunity. This tumor surveillance mechanism is mediated by infiltrating immune cells such as natural killer (NK) and T cells through IFN signaling. Importantly, mounting evidence show that cGAS-STING signaling has also its bad side and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment. In the liver, whereas studies underlined that overactivation of cGAS-STING may contribute to the development of liver disorders, it is still undefined how cGAS/STING signaling acts in HCC harboring different levels of genomic instability. In that context, our team is now interested to explore the interplay between DDR and the cGAS/STING pathway in HCC development, notably in a MASLD context.
OBJECTIVES: The PhD will: (1) Investigate whether STING signaling displays tumor suppressive or promoting functions. (2) Elucidate how STING inhibition impacts on immune landscape of HCC in a MASLD context. (3) Explore how STING signaling according to DNA lesion accumulation is correlated to human HCC development. The PhD student will benefit from a highly collaborative and diverse environment at the Centre de Recherche des Cordeliers and from state-of-the-art technological approaches (e.g. multispectral imaging, RNA Seq, primary culture of hepatocytes, dynamic metabolic approaches). The Centre de Recherche des Cordeliers is located in the center of Paris
Compétences requises:
- Animal experimentation (mouse models)
- Flow cytometry
- Histology
- Cell and molecular biology
- Bioinformatics
Références bibliographiques:
Llovet, J. M. et al. Hepatocellular carcinoma. Nat Rev Dis Primers 7, 6 (2021).
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 16, 411–428 (2019).
Donne, R. et al. Replication stress triggered by nucleotide pool imbalance drives DNA damage and cGAS-STING pathway activation in NAFLD. Developmental Cell (2022) doi:https://doi.org/10.1016/j.devcel.2022.06.003.
Shimizu, I., Yoshida, Y., Suda, M. & Minamino, T. DNA damage response and metabolic disease. Cell Metab 20, 967–977 (2014).
Peiseler, M. et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits. Journal of Hepatology 77, 1136–1160 (2022).
Jneid, B. et al. Selective STING stimulation in dendritic cells primes antitumor T cell responses. Sci. Immunol. 8, eabn6612 (2023).
Ruiz de Galarreta, M. et al. β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov 9, 1124–1141 (2019).
Molina-Sánchez, P. et al. Cooperation Between Distinct Cancer Driver Genes Underlies Intertumo Heterogeneity in Hepatocellular Carcinoma. Gastroenterology 159, 2203-2220.e14 (2020).
Gallage, S. et al. A researcher’s guide to preclinical mouse NASH models. Nat Metab 4, 1632–1649 (2022).
Li, T., and Chen, Z.J. (2018). The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 215, 1287-1299.
