Francais

Summary

Genetic and phenotypic plasticity of cancer

Team Leader :

 

Charles Theillet

                           

Claude Sardet
 

Institut de Recherche en
Cancérologie de Montpellier
Campus Val d’Aurelle
34298 Montpellier cedex 5
 
 
 

 

Tél. : 33 (0)4 67 61 37 66
Fax : 33 (0)4 67 61 30 41
charles.theillet@inserm.fr

claude.sardet@inserm.fr

 
Research topics
 

The "Genetic and Phenotypic Plasticity of Cancer" team is led jointly by C Sardet (also Director of IRCM) and C Theillet, who merged their former labs at IGMM (C Sardet) and IRCM (C Theillet) in 2015. The new team, combines expertise on cellular metabolism, signaling, cell cycle checkpoints and transcriptional control (CS) and on breast and ovarian cancer genetics and cancer cell biology (CT). It has strong and long lasting ties with the clinics, illustrated by fruitful collaborations with Prof W Jacot, head of medical oncology and specialist of breast cancer, and Prof PE Colombo, oncosurgeon at ICM with a special interest in ovarian cancers, who have joined the team.

 

Projects are centered on Triple Negative Breast Cancer (TNBC) and High Grade Ovarian Cancer (HGOC), two aggressive female cancers, which respectively represent about 500 and 50 new patients treated at the ICM every year. Interestingly, despite their very different natural histories, both cancers share genetic characteristics such as the predominance of p53 mutations and the frequent inactivation of the BRCA pathway. For both cancers chemotherapy remains the sole therapeutic option and sustained remissions in advanced forms of the disease are rare. Therefore, the development of new treatment options is an urgent need. We aim at discovering novel Achilles’ heels for these aggressive cancers and build on them to explore novel therapeutic avenues based on synthetic lethality in order to eradicate the tumors along with cancer stem cells. Projects are built on our outstanding collection of 97 comprehensively characterized (omics, drug sensitivity) breast cancer and high grade ovarian carcinoma (HGOC) PDX models, as well as by a collection of genetically modified HMEC and TNBC cancer cell line models. The team is perfectly fluent in CSC biology and isolation of CSCs from both PDX and cancer cell lines.

 

Scientific projects are organized around three major lines of work :

 

1. Characterize and target key determinants of the tumor initiating or cancer “stem” cells (TIC/CSC) subpopulations in TNBC and target them with the aim to reduce risk of recurrence. 

 

2. Exploit the exquisite sensitivity of BRCA-deficient tumor cells to replication stress and characterize the principal actors, as well as conditions that maximizes it. In particular, we will focus on the interactions of BRCA1 with CDK1/2 and test whether we can produce a pharmacological BRCA-deficiency in BRCA1 wild type cancers. 

 

3. Explore poorly-described metabolic reprogramming mechanisms in TNBC, specifically aiming the mitochondrial steps of the pyrimidine neosynthesis and of the proline neosynthesis/catabolism, two metabolic pathways under the control of bona fide oncogenes and tumor suppressors. Specific synthetic-lethal interactions with cell cycle checkpoints have been identified and are explored and targeted.

 

 


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Main Publications

 

Fonti C, Saumet A, Abi-Khalil A, Orsetti B, Cleroux E, Bender A, Dumas M, Schmitt E, Colinge J, Weber M, Sardet C, Du Manoir S, Theillet C (in revision, biorxiv, https://doi.org/10.1101/344465) Distinct oncogenic events induces different DNA methylation and copy number changes in human mammary epithelial cells.

 

Kreuzinger C, Geroldinger A, Smeets D, Braicu EI, Sehouli J, Koller J, Wolf A, Darb-Esfahani S, Joehrens K, Vergote I, Vanderstichele A, Boeckx B, Lambrechts D, Gabra H, Wisman G, Trillsch F, Heinze G, Horvat R, Polterauer S, Berns E, Theillet C & Cacsire Castillo-Tong D. (2017) Molecular characterization of primary and recurrent high grade serous ovarian cancer. Clin Cancer Res 23(24):7621-7632.

 

Arnould S, Rodier G,  Matar G , Vincent C , Pirot N , Delorme Y , Berthet C, Buscail Y , Noel JY , Lachambre S , Jarlier M, Bernex F,  Delpech H , VIdalain PO, Janin Y,  Theillet C, &  Sardet C (2017) Checkpoint kinase 1 inhibitor sensitises transformed cells to dihydroorotate dehydrogenase inhibition. Oncotarget. Jul 12;8(56):95206-95222

 

Lacroix M*, Rodier G*, Kirsh O, Houles T, Delpech H, Seyran B, Gayte L, Casas F, Pessemesse L, Heuillet M, Bellvert F, Portais JC, Berthet C, Bernex F, Brivet M, Boutron A, Le Cam L* & Sardet C* (2016) E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity. Proc Natl Acad Sci U S A.  Sep 27;113(39):10998-1003.

 

Rodier G, Kirsh O, Baraibar M, Houlès T, Lacroix M,  Delpech H, Hatchi E, Arnould S, Severac D, Dubois E, Caramel J, Julien E, Friguet B, Le Cam L*,  Sardet C*. (2015) The Transcription Factor E4F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial Functions. Cell Reports. 14;11(2):220-33.  * co-senior/ corresponding authors

 

Du Manoir S, Orsetti B, Bras-Gonçalves R, Nguyen TT,  Lasorsa L, Boissière F, Massemin B,  Colombo PE, Bibeau ,  Jacot W, Theillet C. Breast tumor PDXs are genetically plastic and correspond to a subset of aggressive cancers prone to relapse. Mol Oncol. 2014 Mar;8(2):431-43

 

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