Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors derived from chromaffin cells of the adrenal medulla and paraganglia of the autonomic nervous system, respectively. Despite a common origin, these tumors are quite heterogeneous in terms of driver mutations, copy number alterations and activated downstream-signaling pathways. Genome wide expression analysis has identified at least three main tumor clusters: a pseudo-hypoxic cluster, one with activation of wnt-signaling and one with enhanced kinase-signaling. Further subgrouping has been suggested according to molecular, clinical and pathological phenotypes. Tumors in the pseudo-hypoxic Cluster 1 present a marked increase in cell proliferation and activation of angiogenesis pathways. Several genes predispose to Cluster 1 tumors, including VHL, EPAS1, FH and SDHx, but for some patients the underlying genetic mutation could not be identified. Surprisingly, targeting these genes in mice did not lead to the development of PPGLs. Our unique MENX rat model, carries a germline mutation in Cdkn1b, coding for a highly unstable variant of the cell cycle inhibitor p27. MENX rats develop bilateral pheochromocytomas with 100% penetrance: at 810 months of age the homozygous mutant; >15 months the heterozygotes. Following genome-wide transcriptomic analyses and candidate gene profiling we observed that the rat tumors display expression signatures characteristic of Cluster 1 human pheochromocytomas. These include increased expression of angiogenesis markers like VEGF and ANGPT2 and pseudohypoxic markers as HIF2a. Moreover, lack of PNMT expression and catecholamine secretion in these rats are also in line with a pseudo-hypoxic phenotype. We therefore hypothesize that in MENX rats defective p27 function predisposes to the development of pheochromocytomas resembling human Cluster 1 tumors. Thus, these rats might lead to new insights into the pathomechanism of Cluster 1 tumor formation. Moreover, they offer a unique opportunity to preclinically evaluate drugs for efficacy against this specific subset of PPGLs.
18 - 21 May 2019
European Society of Endocrinology