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Molecular méchanisms of secretion in neuroendocrine tumors

Research unit

UPR 3212 - Institut des Neurosciences Cellulaires et Intégratives (INCI)
5, rue Blaise Pascal, 67084 STRASBOURG

Group

Name: Trafic membranaire dans les cellules du système nerveux

Group leader: GASMAN/VITALE Stéphane/nicolas - gasman@unistra.fr/vitalen@unistra.fr

Group leader's phone: 0388456712

Website: Visit website

Group organization:
- Chercheurs: 8
- ITA: 4
- Doctorants: 4
- Post-Docs: 0
- Autres: 0

Publications of the team linked to the topic (3 last years):
1) Croisé P, Houy S, Gand M, Lanoix J, Calco V, Tryoen-Tóth P, Brunaud L, Lomazzi S, Paramithiotis E, Chelsky D, Ory S and Gasman S. Cdc42 and Rac1 activity is reduced in human pheochromocytoma and correlates with FARP1 and ARHGEF1 expression. Endocr. Relat. Cancer 2016, Feb 24. pii: ERC-15-0502. [Epub ahead of print].
2) Houy S, Estay-Ahumada C, Croisé P, Calco V, Haeberlé AM, Bailly Y, Billuart P, Vitale N, Bader MF, Ory S, Gasman S. Oligophrenin-1 connects exocytotic fusion to compensatory endocytosis in neuroendocrine cells. J. Neurosci. 2015, 2015 Aug 5;35(31):11045-55. doi: 10.1523/JNEUROSCI.4048-14.2015.
3) Croisé P, Estay-Ahumada C, Gasman S, Ory S. RhoGTPases, phosphoinositides, and actin: A tripartite framework for efficient vesicular trafficking. Small GTPases. 2014 Jun 10;5.

About PhD

PhD Director: GASMAN Stéphane - gasman@unistra.fr

Phone: 0388456712

Junior advisor: ORY Stéphane

Co-tutely: non

Co-Director: non

About PhD topic :

Title: Molecular méchanisms of secretion in neuroendocrine tumors

Project: Neuroendocrine cells secrete hormones and neuropeptides through calcium-regulated exocytosis, a process that involves sequential steps including the recruitment of secretory granules to the plasma membrane, their docking at the exocytotic sites and their subsequent fusion with the plasma membrane leading to the release of secretory products into the extracellular space. Exocytosis needs to be tightly controlled since dysregulated secretion from neuroendocrine cells is associated to various pathologies including cancer.

Neuroendocrine tumors (NETs) are neoplasms arising from hormone/peptide-secreting cells. Although NETs are heterogeneous, a common critical feature is the dysfunction of the secretory activity leading to hypersecretion. While hypersecretion by NETs is well known to pathologists and clinicians, it has never been explored at the cellular and molecular level in human tumor cells. Investigating such mechanisms is important since hormone/peptide hypersecretion leads to severe clinical manifestations and may favor tumor development.
Pheochromocytomas are NETs that arise from chromaffin cells of the adrenal medulla, which are characterized by an excess of catecholamine secretion, leading to hypertension, cardiomyopathy and high risk of stroke. Carcinoid tumors from the gastro-intestinal tract are endocrine neoplasms derived from the neuroectodermal enterochromaffin cells (EC-carcinoid tumors) that hypersecrete serotonin and can cause the carcinoid syndrome, with characteristic symptoms of flushing, diarrhea, bronchoconstriction, and cardiac valvular disease. Using these two models, the main objective of this Ph.D project is to understand the cellular and molecular bases of the secretory dysfunction in order to attempt to inhibit tumor-associated hypersecretion in human cells. To achieve these objectives, we propose an innovative multidisciplinary approach combining carbon fiber amperometry, bioinformatics and advance quantitative mass spectrometry. More precisely, to investigate which step(s) of the secretory process is/are disturbed, we will apply on primary culture of human pheochromocytoma and EC-carcinoid tumor cells, carbon fiber amperometry, a technique that enables precise measurement of individual exocytotic event dynamics in real time. Finally, the detection in these tumors of exocytotic protein expression changes by mass spectrometry, coupled to bioinformatic and functional analyses of their role in tumor secretion will allow us to propose key protein candidates that could be potentially targeted to inhibit tumor-associated-hypersecretion.

Wished skills: The student should have a good knowledge in cell biology and a strong interest for the membrane trafficking processes in general. The candidate can have been equally trained in a Master of cell biology or Neurosciences. A good interest in cancer biology will be also required.

Expertises which will be acquired during the training: The multidisciplinary aspect of this project will allow the student to acquire an important panel of technical expertises including biochemistry and cellular and molecular biology. By leading this project, the student will get a strong conceptual expertise in the field of membrane trafficking and cancer biology. Moreover, this Ph.D training will allow the candidate to further manage any cell biology project in the future.