Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis

嗜铬细胞瘤和副神经节瘤是产生儿茶酚胺的神经内分泌肿瘤，起源于肾上腺和肾上腺外嗜铬细胞组织。根据至少11个基因中任何一个的潜在突变，这些肿瘤具有高度异质性的表现。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，并通过临床相关基因的分子操作建立了新的肿瘤细胞模型系统。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，在诊断测试方面取得了进展。使用我们的PPGL模型系统，我们发现了一条以前未知的途径，解释了由于MYC相关因子X(MAX)和其他PPGL易感基因的突变而在PPGL中观察到的各种特征。我们的研究发现，HIF1和HIF2通过MYC/MAX相关途径在肿瘤发生过程中发挥不同作用，这一发现将在第二个资助期延长，以更全面地描述这一途径的确切机制，并将重点放在临床研究上，HIF2是最近发现的肿瘤易感基因之一。我们将进一步利用我们的基因操纵的嗜铬肿瘤细胞模型系统来开发PPGL的小鼠模型，这些模型概括了人类疾病的潜在发展过程，从而为针对临床相关途径的实验性治疗干预提供了合适的工具。

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.