Senescence, fibrosis and cancer
UMR Canther CNRS 9020 – Inserm S 1277 – Lille University – CHU de Lille – Institut Pasteur de Lille
Phase contrast micrography of a senescent human skin keratinocyte surrounded by emerging precancerous cells.
The team is composed of Researchers, Professors, Clinicians, Engineers and Technicians joining their expertise, workforce and resources to develop basic and translational research programs on the impact of the two main forms of cellular aging (cellular senescence and fibrosis) on cancer initiation as well as on cancer recurrence after treatment. In this context, the objectives of the team are (1) to decipher the interrelationships between the molecular mechanisms of senescence and fibrosis, (2) to analyze their impact on tumorigenesis in the context of aging, (3) to understand whether and how anti-cancer therapy-induced senescence and fibrosis could contribute to anti-cancer treatment resistance, tumor dormancy, and tumor relapse, and (4) to search for new seno-fibrolytics drugs that could eliminate senescent and/or fibrotic cells to decrease their impacts.
- The project in collaboration with the group of Réjane Paumelle (U1011 – EGID), supported by the CPER « Centre Translationnel de Recherche sur le Longévité » gave rise to a publication in Decembre 2020 in Journal of Biological Sciences (Deleye et al. (2020). J Biol Chem. 295:17310).
- The project concerned nonalcoholic steatohepatitis (NASH), a severe liver disease potentially evolving in cirrhosis and hepatocellular carcinoma. Age is a risk factor for NASH, however the underlying mechanisms are not clearly defined. Our hypothesis was that cellular senescence, characterized by p16INK4a expression, may be a potential mediator of the disease progression. In this work, we show that p16 overexpression induces triglyceride accumulation and increased lipid droplet number in hepatocytes. However, a concomitant induction of cellular senescence was not demonstrated.
- The results of Christelle Cauffiez, Nicolas Pottier and François Glowacki regarding the Cadmium nephrotoxicity have been published in April 2020 in International Journal of Toxicology (Lemaire J et al. Int J Toxicol. 2020 Mar/Apr;39(2):103-114). In this work, the group showed that cadmium exposure in renal cell models results in cytotoxicity associated with morphological changes, overexpression of renal injury markers, induction of apoptosis, and inflammation. Cadmium exposure also resulted in the significant upregulation of 38 miRNAs, most of them being known to target genes encoding proteins involved in oxidative stress, inflammation, and apoptosis.
- Amélie Decourcelle defended her PhD dissertation in decembre 11, 2020. The general context of her work, done under the supervision of Vanessa Dehennaut, was on the connection between nutrition, epigenetics and colo-rectal cancer. She worked on the regulation of UNC5A, a dependance receptor involved in apoptosis, by the epienzyme EZH2, itself regulated by O-GlucNacylation, a glycosylation sensor of nutrient stress. Her work gave rise to 3 publications : Cancers 2020, Biochem Biophys Res Commun. 2020; Front Endocrinol 2019.
Impact and regulation of intestinal epithelial cell senescence during gut wound healing (2017-2018, Corinne Abbadie, in collaboration with Mathias Chamaillard, U 1003). Along aging, the cells that constitute our organs loss their capacity to divide and renew, abundantly secrete pro-inflammatory molecules, and become unable to repair the damages affecting their chromosomes, hence becoming potentially tumorigenic. Thereby, they contribute to most age-associated disorders and pathologies. The capacity to repair an injury of the gut declines with age, potentially leading to chronic Inflammatory Bowel Diseases and colorectal cancer. In this project, we have evaluated the role of two potential new actors of the gut wound healing, NLRP6 and CSNK2.
Role of CDKN2A/p16INK4a on lipid metabolism and senescence in hepatocytes : impact on NASH development during aging (2017-2018, Réjane Paumelle (UMR1011) in collaboration with Albin Pourtier). The most common liver disease, affecting one third of the overall population, is nonalcoholic fatty liver disease (NAFLD), characterized by an intrahepatic accumulation of lipids (steatosis) which can evolve into nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma. To date, no effective medical treatments for NASH are available, only life style intervention or weight loss surgery is proposed. The prevalence of NAFLD in general population increases with age, over 40% in those greater than 70 years. In this project, we have investigated the role of p16, an inducer of cellular senescence, in the induction of the pathology.
Role of the UPR pathway in fibrosis associated to aging (2018-2019, Olivier Pluquet, in collaboration with Nicolas Pottier). Aging represents a major risk factor for pulmonary fibrosis. Little is known on the cellular and molecular mechanisms underlying fibrosis during aging, in particular, the role of senescence, a cellular aging process. In this project, we examined whether senescence and fibrosis lead to two distinct phenotypes or co-exist as a mixed phenotype.
Role of FAT10 in hepatocyte senescence : impact on NASH development (2020-2021, Réjane Paumelle (U1011) in collaboration with Albin Pourtier). This project concerns again nonalcoholic steatohepatitis (NASH). Cellular senescence may be a potential mediator of disease progression. We have shown that senescent hepatocytes overexpress FAT10. Our project aims to determine the role of FAT10 expression in hepatocyte senescence and its link with lipid metabolic alterations and steatosis development.
Professor, Univ Lille
ORCID number : 0000-0002-8174-2393
Yvan DE LAUNOIT
Research director, CNRS
ORCID number : 0000-0003-1837-9808
Research director, CNRS
ORCID number : 0000-0002-1999-0775
Professor, Univ Lille
ORCID number : 0000-0003-0951-7973
Nephrologist, CHU Lille – PU, Univ Lille
ORCID number : 0000-0001-5443-9172
Biologist, CHU Lille – MCU, Univ Lille
ORCID number : 0000-0001-8913-6286
MCU, Univ Lille
ORCID number : 0000-0002-1576-3946
MCU, Univ Lille
ORCID number : 0000-0001-5178-0076
MCU, Univ Lille
ORCID number : 0000-0001-6421-0793
ORCID number : 0000-0001-8021-2676
Cynthia VAN DER HAUWAERT
Engineer, CHU Lille
Engineer, Univ Lille
Engineer assistant, CNRS
Clémentine DE SCHUTTER
Engineer, CNRS (CDD)
Abbadie C, Pluquet O.
Unfolded Protein Response (UPR) Controls Major Senescence Hallmarks.
Trends Biochem Sci. 2020 May;45(5):371-374. doi: 10.1016/j.tibs.2020.02.005. Epub 2020 Mar 4. PMID: 32311331.
Lemaire J, Van der Hauwaert C, Savary G, Dewaeles E, Perrais M, Lo Guidice JM, Pottier N, Glowacki F, Cauffiez C.
Cadmium-Induced Renal Cell Toxicity Is Associated With MicroRNA Deregulation.
Int J Toxicol. 2020 Mar/Apr;39(2):103-114. doi: 10.1177/1091581819899039. Epub 2020 Jan 14. PMID: 31934807.
Savary G, Dewaeles E, Diazzi S, Buscot M, Nottet N, Fassy J, Courcot E, Henaoui IS, Lemaire J, Martis N, Van der Hauwaert C, Pons N, Magnone V, Leroy S, Hofman V, Plantier L, Lebrigand K, Paquet A, Lino Cardenas CL, Vassaux G, Hofman P, Günther A, Crestani B, Wallaert B, Rezzonico R, Brousseau T, Glowacki F, Bellusci S, Perrais M, Broly F, Barbry P, Marquette CH, Cauffiez C, Mari B, Pottier N.
The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis.
Am J Respir Crit Care Med. 2019 Jul 15;200(2):184-198. doi: 10.1164/rccm.201807-1237OC. PMID: 30964696.
Van der Hauwaert C, Glowacki F, Pottier N, Cauffiez C.
Non-Coding RNAs as New Therapeutic Targets in the Context of Renal Fibrosis.
Int J Mol Sci. 2019 Apr 23;20(8):1977. doi: 10.3390/ijms20081977. PMID: 31018516; PMCID: PMC6515288.
Pluquet O, Abbadie C, Coqueret O.
Connecting cancer relapse with senescence.
Cancer Lett. 2019 Oct 28;463:50-58. doi: 10.1016/j.canlet.2019.08.004. Epub 2019 Aug 9. PMID: 31404612.
Senescence ; Fibrosis ; Cancer ; Keratinocytes ; Fibroblasts ; MicroRNA ; Non-coding RNA ; Oxydative stress ; DNA Damage ; Radiotherapy ; Chemotherapy ; Lungs ; Kidneys ; Skin
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