JCJC SVSE 1 - JCJC - SVSE 1 - Physiologie, physiopathologie, santé publique

Mlecular Deciphering Of Malignancy in Pheochromocytoma and Paranganglioma – MODEOMAPP

Submission summary

Pheochromocytomas (PHEO) and paragangliomas (PGL) are tumours that arise from chromaffin tissues of the adrenal medulla and sympathetic and parasympathetic ganglia. They are malignant in 15% of cases and hereditary in 30% of cases. Hereditary PHEO/PGL are caused by germline mutations in one of the 9 PHEO/PGL susceptibility genes: VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127. Mutations in SDHB gene are responsible for metastatic form of the disease and are associated with poor prognosis.
The aim of this MODEOMAPP project is to decipher the molecular mechanisms responsible for PHEO/PGL malignancy, with a particular interest in inherited forms associated with SDHB gene mutations. The completion of this project will require the generation of cell and animal models of SDHB-dependant malignant PHEO/PGL to progress in understanding mechanisms of tumorigenesis and carcinogenesis and validate new therapeutic strategies for these tumours for which surgery remains the only curative treatment.
We develop mouse ES and chromaffin cell models in which SDHB will be inactivated by a Cre/lox strategy. Mice harbouring SDHB constitutive or conditional inactivation have also been generated and will be crossed with different lines of transgenic or knockout mice (PSA-Cre, Bloom, PTEN +/-) and/or subjected to conditions of environmental stress (hypoxia), which should accelerate the development of tumours and increase their invasiveness and metastatic potential. Non-invasive evaluation of tumour burden and vascularization will be assessed by MRI on the PARCC’s small animal imaging platform.
The analysis of the transcriptome of 200 human PHEO/PGL has revealed differentially expressed genes in SDHB-related malignant PHEO/PGL. Among these genes, LOXL2 and TWIST appeared particularly interesting. They are involved in epithelial-mesenchymal transition, a process that participates to the invasiveness of different types of metastatic cancers. In order to obtain an increased statistical power, and a validation cohort, the transcriptome data will be combined with those obtained by Prof. R de Krijger in Rotterdam. The evaluation of chromosomal rearrangements (BAC array CGH and SNP- array), alterations of the DNA methylation pattern (methylome) and modification of microRNA expression profile (miRnome) will complete this meta-analysis. This ‘OMICs’ characterization of genomic and genetic events associated with SDHB-related malignancy will lead to the identification of candidate pathways that will then be functionally validated. After confirming their comparable regulation in SDHB-related cell and animal models, the effect of their silencing by siRNA approaches will be tested on proliferation, migration, survival, and the ability of these cells to form vascularised tumours in vivo. In mice that spontaneously develop tumours, pre-clinical trials assessing the role of these targets may be launched. Finally, prognostic biomarkers will be validated and transferred to clinics as tools to predict the malignant potential of a PHEO/PGL from initial pathological analysis of the primary tumour and to implement the first international clinical trial of targeted therapy in malignant PHEO/PGL and select patients for inclusion in this trial. This project will be a major asset to the neuroendocrine cancer field, with the development and analysis of in vitro and preclinical mouse models, essential to various projects of basic and applied research.

Project coordination

Judith FAVIER (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE DE PARIS V) – judith.favier@inserm.fr

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DELEGATION REGIONALE DE PARIS V

Help of the ANR 301,920 euros
Beginning and duration of the scientific project: February 2012 - 48 Months

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