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Subject of the thesis

Endothelial cell reprogramming in cancer microenvironment: Towards the identification of new therapeutic targets

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Published on 10 March 2020

Summary of the project
This project aims at understanding the consequences of VE-cadherin modifications on Endothelial Cells functions in cancer. In the laboratory we have produced a new Y685F-VE-cadherin knock-in mouse (KI) in which all VEcadherin molecules are mutated on the tyrosine 685 (replaced by the non phosphorylable amino acid phenylalanine). Mutated ECs will be isolated from this mouse model, then analysed for their morphology, and functions. EC will be grown to perform several types of assays such as Cell culture wound closure assay, EC co-culture spheroids, the real-time random migration assay to measure migration and 3D models of vascular morphogenesis. The expressional effect of the mutation at site Y685 of VE-cadherin will be analysed by RNAseq to examine the transcriptome of purified ECs from Wild type and KI. The gene expression data generated by RNA-seq will be analyzed using Gene Set Enrichment Analysis to extract biological knowledge with critical keywords for the gene-sets such as cloating, inflammation, mitosis, fibrosis as they are linked with EC functions. Based on the results of the gene expression, the physiopathological analysis of specific organs of the KI mouse model will be performed. The new activated gene panel might identify new EC functions in the tumor context that can represent new potential targets in therapeutics.

Keywords
endothelial cell functions, tyrosine kinases, phosphorylations, gene expression, VE-cadherin

Applicant profile

Candidates should have a strong background in physiology, cell signalling, and biochemistry.
Preliminary experience in mouse models will be a key advantage.


Three recent publications of the PhD supervisor
Polena H, Creuzet J, Dufies M, Sidibé A, Khalil-Mgharbel A, Salomon A, Deroux A, Quesada JL, Roelants C, Filhol O, Cochet C, Blanc E, Ferlay-Segura C, Borchiellini D, Ferrero JM, Escudier B, Négrier S, Pages G, Vilgrain I. The tyrosinekinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma. Br J Cancer. 2018 May;118(9):1179-1188
Khalil-Mgharbel A, Polena H, Dembélé PK, Hasan Sohag MM, Alcaraz JP, Martin DK, Vilgrain I. A Biomimetic Lipid Membrane Device Reveals the Interaction of Cancer Biomarkers with Human Serum Lipidic Moieties. Biotechnol J. 2018 Dec;13(12):e1800463
Rochefort P, Chabaud S, Pierga JY, Tredan O, Brain E, Bidard FC, Schiffler C, Polena H, Khalil-Mgharbel A, Vilgrain I, Bachelot T. Soluble VE-cadherin in metastatic breast cancer: an independent prognostic factor for both progression-free survival and overall survival. Br J Cancer. 2017;116(3):356-361

More
PhD supervisor and contact: Isabelle Vilgrain
Research institute: IRIG
Laboratory: BCI, UMRS 1036
Research team: Invasion Mechanisms in Angiogenesis and Cancer (IMAC)

GRAL PhD funding includes 3 years of salary (gross salary: 1768.55 € per month) and 10,000€ of bench fees per year. Candidates must directly contact the PhD supervisor(s) to apply.

Schedule
Deadline of the call for PhD projects applications: November 2019
Opening of the call for student applications: Mars 2020
Audition for PhD candidates: May 4th 2020 at IBS, salle des conseils (Grenoble)
Results: May 2020
Registration at Université Grenoble Alpes and start of PhD project: autumn 2020
The candidate selected by the PhD supervisor(s) must send the following documents in a unique pdf file to GRAL’s Executive Manager: Anne-Mathilde Thierry before April 26th (23:59, CET):
• The application file, filled, dated, and signed Download application file
• A cover letter (one page maximum) including ranking obtained during the 1st and 2nd year of Master
• A detailled CV
• A letter of support from the PhD supervisor(s)
• Diploma(s) and copies of academic transcripts equivalent to a 1st year of MSc (or 3-yr BSc and 1 year of MSc), translated to English (or French) if needed
• Copies of academic transcripts equivalent to a 2nd year of MSc, translated to English (or French) if needed
• Level of language proficiency (e.g. TOEIC, Bulats, etc.) if available / appropriate