Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis

嗜铬细胞瘤和副神经节瘤（PPGLs）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染色质组织。肿瘤具有高度异质性的表现，取决于至少11个基因中的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，超过1200名患者入组，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改进的测试策略，诊断测试取得了进展。利用我们的PPGL模型系统，我们发现了一个以前未被认识的途径，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。我们发现HIF1¿和HIF2¿通过MYC/MAX相关途径对肿瘤发生过程的作用不同，将在第二个资助期进行扩展，以更全面地描述该途径的精确机制，并进一步强调HIF2¿作为最近发现的肿瘤易感基因之一的临床研究。我们将进一步利用我们的基因操纵的染色质肿瘤细胞模型系统来开发概括人类疾病潜在发育过程的PPGLs小鼠模型，从而为针对临床相关途径的实验性治疗干预提供合适的工具。

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.