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Role of Huntingtin in the chemoresistance of glioma cancer stem cells

Objectifs

The candidate will i) determine the levels and cellular localization of huntingtin protein in glioma stem cells ii) test a strategy to tamper with these levels and iii) assess chemosensitization in vitro and in vivo.

Résumé

Glioblastoma multiform (GBM) is the most common malignant primary brain tumor with a deadly outcome. Highly infiltrative glioma stem cells (GSCs) escape surgical resection, develop resistance to temozolomide (TMZ), the first-line oral alkylating chemotherapy drug, and are responsible for tumor relapse. We demonstrated in vitro that decreasing the protein levels of huntingtin (HTT) sensitizes glioma cell lines to TMZ. However, whether this strategy sensitizes GSCs from different molecular subtypes of GBM (proneural, classical and mesenchymal subtypes) in vitro and in vivo remain to be established. HTT is a scaffold protein of 348 kDa, widely expressed in the brain. HTT is mutated in the neurodegenerative disorder Huntington's disease (HD). The work that will be undertaken by the M2 trainee candidate will contribute to further clarify the mode of action of our strategy.The candidate will use specific antisense oligonucleotides to decrease HTT mRNA in GSCs. The oligonucleotides have been tested in clinical trials to decrease levels of HTT in HD patients. The candidate will i) evaluate the cytotoxicity of TMZ in the presence of the oligonucleotides, ii) assess the exacerbation of cellular pathways linked to DNA damage, and iii) analyze proliferation and vascularization (histochemistry) in brain tumors obtained during a preclinical test with NUDE mice gratfted with GSCs (collaboration with E Huillard, ICM, Paris) and co-treated with the ASO and TMZ.

Méthodes

Western blot, cell culture, immunocytochemistry, histochemistry, flow cytometry.

Références

Barnat M, Capizzi M, Aparicio E, Boluda S, Wennagel D, Kacher R, Kassem R, Lenoir S, Agasse F, Braz BY, Liu JP, Ighil J, Tessier A, Zeitlin SO, Duyckaerts C, Dommergues M, Durr A, Humbert S (2020). Huntington's disease alters human neurodevelopment. Science, 369(6505):787-793.

Agasse F, Mendez-David I, Christaller W, Carpentier R, Braz BY, David DJ, Saudou F, Humbert S. (2020) Chronic Corticosterone Elevation Suppresses Adult Hippocampal Neurogenesis by Hyperphosphorylating Huntingtin. Cell Rep., 32(1):107865.

Jhaveri N, Agasse F, Armstrong D, Peng L, Commins D, Wang W, Rosenstein-Sisson R, Vaikari VP, Santiago SV, Santos T, Chen L, Schönthal AH, Chen TC, Hofman FM (2016). A novel drug conjugate, NEO212, targeting proneural and mesenchymal subtypes of patient-derived glioma cancer stem cells. Cancer Lett. 371(2):240-50.

Domaines d'expertise requis

Cellular biology, histology, neuroscience, biology of the cancer cell.

Contacts

F. Agasse (HDR, MCU UGA) et L. Ratié
Email : fabienne.agasse@univ-grenoble-alpes.fr, leslie.ratie@univ-grenoble-alpes.fr
Phone : 04 56 52 05 11 / 04 56 52 05 67

Téléchargement(s)

GIN_offre-stage-M2_2022-2023_AAgasse-LRatié_20220707.pdf (PDF, 109458 Ko)

Mise à jour le 8 juillet 2022

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