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Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis

嗜铬肿瘤发生中的缺氧和 MYC/MAX 信号通路

基本信息

批准号：
202068244
负责人：
Professor Dr. Graeme Eisenhofer, Ph.D.
金额：
--
依托单位：
Medizinische Klinik und Poliklinik III
依托单位国家：
德国
项目类别：
Clinical Research Units
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/202068244?language=en
关键词：
Hypoxia MYC MAX signaling pathways

项目摘要

Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine-producing neuroendocrine tumours that derive from adrenal and extra-adrenal chromaffin tissue. The tumours have highly heterogeneous presentations depending on underlying mutations to any of at least 11 genes. This project combines clinical observational and preclinical mechanistic studies that in the first funding period enabled enrolment of over 1200 patients and establishment of novel tumour cell model systems with molecular manipulations of clinically relevant genes. From our patient studies there have been advances in diagnostic testing based on newly developed methods and refinements to testing strategies. Using our PPGL model systems we have uncovered a previously unrecognised pathway that explains the varied features observed in PPGLs due to mutations of MYC-associated factor X (MAX) and other PPGL susceptibility genes. Our findings that HIF1¿ and HIF2¿ act differentially on tumourigenic processes via a MYC/MAX related pathway will be extended in the second funding period to more fully delineate the precise mechanisms of this pathway, with additional emphasis on clinical studies focussed on HIF2¿ as one of the most recently identified tumour-susceptibility genes. We will further utilise our genetically-manipulated chromaffin tumour cell model systems for development of murine models of PPGLs that recapitulate underlying developmental processes of human disease, thereby providing a suitable tool for experimental therapeutic interventions that target clinically relevant pathways.

嗜铬细胞瘤和副神经节瘤（PPGL）是产生儿茶酚胺的神经内分泌肿瘤，来源于肾上腺和肾上腺外的嗜铬组织。肿瘤具有高度异质性表现，这取决于至少11个基因中任何一个的潜在突变。该项目结合了临床观察和临床前机制研究，在第一个资助期内招募了1200多名患者，并通过对临床相关基因的分子操作建立了新型肿瘤细胞模型系统。从我们的患者研究中，基于新开发的方法和对测试策略的改进，诊断测试取得了进展。使用我们的PPGL模型系统，我们发现了一个以前未被识别的途径，该途径解释了由于MYC相关因子X（MAX）和其他PPGL易感基因突变而在PPGL中观察到的各种特征。我们的研究结果表明，和HIF 2？通过MYC/MAX相关途径对肿瘤发生过程产生差异作用的研究将在第二个资助期内延长，以更全面地描述该途径的确切机制，并将重点放在最近发现的肿瘤易感基因之一HIF 2？的临床研究上。我们将进一步利用我们的基因操纵嗜铬肿瘤细胞模型系统开发小鼠模型的PPGL，重演人类疾病的潜在发展过程，从而提供一个合适的工具，实验治疗干预措施，目标临床相关的途径。