Project Details
Projekt
Hypoxia and MYC/MAX signaling pathways in chromaffin tumourigenesis
Applicant
Professor Graeme Eisenhofer, Ph.D.
Subject Area
Endocrinology, Diabetology, Metabolism
Term
from 2011 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 189897882
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.
DFG Programme
Clinical Research Units
Participating Person
Professor Jacques W.M. Lenders, Ph.D.
