Our research project at a glance
We are studying the role of cholesterol metabolism in the control or progression of cancers and in resistance to therapies, with a particular focus in breast cancer.
We want to identify and validate new therapeutic targets, to identify new mechanisms of resistance to treatments and to improve outcome through a better stratification of cancers.
Specifically, we are studying the contribution of cholesterol metabolism in the response to the endocrine therapy with Tamoxifen (Tam) and aromatase inhibitors (AI). We identified a new metabolic pathway centered on cholesterol-5,6-epoxide hydrolase (ChEH). ChEH controls cholesterol-5,6-epoxide (5,6-EC) metabolism and is a direct target of Tam (de Medina et al, PNAS 2010). We showed its importance in the anticancer action of Tam. ChEH controls the production of metabolites with opposite properties in cancers.
We have first identified dendrogenin A (DDA), an amino-oxysterol tumor suppressor produced by healthy tissues (de Medina et al, Nat Commun 2013). Recently we discovered an onco-metabolite tumor promoter produced by cancer cells. The identification of these two end-products of the cholesterol metabolism with opposite properties opens up new perspectives for the development of novel therapies. It will help to understand fine mechanisms involved in acquired and intrinsic resistances to various therapies (Silvente-Poirot & Poirot, Science 2014).
Our objectives are :
- to characterize the molecular actors controlling this metabolic pathway,
- to elucidate the mechanism of action of these new metabolites, including their impact on exosome production and phenotypes,
- to characterize their impact on the tumor microenvironment (in particular on the immune system).
Our objectives are also to propose innovative therapeutic approaches to counter or circumvent resistances to therapy and to identify new surrogate biomarkers of responses.
Our approach links basic research to medical applications with a goal of valorization in partnership with our spin off, Affichem (9 patents filed over the last 5 years).
- Cholesterol biosynthesis
- Cholesterol metabolism
- Cholesterol-5,6-epoxide hydrolase
- Cholesteryl esters
- Nuclear receptors
- Medicinal chemistry
- Cell differentiation
- Cell death
- Immune system
- Tumor suppressor
- Tumor promoter
Labels and networks
Grants and funders
Biochem Pharmacol, 144 , pp. 18-28, 2017, ISSN: 1873-2968 (Electronic) 0006-2952 (Linking).
Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor Journal Article
Proc Natl Acad Sci U S A, in press , 2017.
Chem Phys Lipids, 207 (Pt B), pp. 92-98, 2017, ISSN: 1873-2941 (Electronic) 0009-3084 (Linking).
Biochimie, 130 , pp. 109-114, 2016, ISSN: 1638-6183 (Electronic) 0300-9084 (Linking).
Cancer. Cholesterol and cancer, in the balance Journal Article
Science, 343 (6178), pp. 1445-6, 2014, ISSN: 1095-9203 (Electronic) 0036-8075 (Linking).
Nat Commun, 4 , pp. 1840, 2013, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).
Cholesterol epoxide hydrolase and cancer Journal Article
Curr Opin Pharmacol, 12 (6), pp. 696-703, 2012, ISSN: 1471-4973 (Electronic) 1471-4892 (Linking).
Biochem Pharmacol, 81 (10), pp. 1171-82, 2011, ISSN: 1873-2968 (Electronic) 0006-2952 (Linking).
Proc Natl Acad Sci U S A, 107 (30), pp. 13520-5, 2010, ISSN: 1091-6490 (Electronic) 0027-8424 (Linking).
J Med Chem, 52 (23), pp. 7765-77, 2009, ISSN: 1520-4804 (Electronic) 0022-2623 (Linking).