Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma
- Sara Molatore1,*,
- Andrea Kügler1,*,
- Martin Irmler2,
- Tobias Wiedemann1,
- Frauke Neff2,
- Annette Feuchtinger3,
- Johannes Beckers2,4,5,
- Mercedes Robledo6,
- Federico Roncaroli7 and
- Natalia S Pellegata1⇑
- 1Institute for Diabetes and Cancer, Helmholtz Zentrum München, Neuherberg, Germany
- 2Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany
- 3Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany
- 4German Center for Diabetes Research (DZD), Neuherberg, Germany
- 5Technische Universität München, Chair of Experimental Genetics, Freising, Germany
- 6Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
- 7Division of Neuroscience and Experimental Psychology, Faculty of Medicine, University of Manchester, Manchester, UK
- Correspondence should be addressed to N S Pellegata: natalia.pellegata{at}helmholtz-muenchen.de
Abstract
Rats affected by the MENX syndrome spontaneously develop multiple neuroendocrine tumors (NETs) including adrenal, pituitary and thyroid gland neoplasms. MENX was initially reported to be inherited as a recessive trait and affected rats were found to be homozygous for the predisposing Cdkn1b mutation encoding p27. We here report that heterozygous MENX-mutant rats (p27+/mut) develop the same spectrum of NETs seen in the homozygous (p27mut/mut) animals but with slower progression. Consequently, p27+/mut rats have a significantly shorter lifespan compared with their wild-type (p27+/+) littermates. In the tumors of p27+/mut rats, the wild-type Cdkn1b allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression in this model. Transcriptome profiling of rat adrenal (pheochromocytoma) and pituitary tumors having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage vs early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs and found to be associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive and metastatic MTC exploitable for translational studies of this often aggressive and incurable cancer.
- Received 9 November 2017
- Accepted 15 November 2017
- Made available online as an Accepted Preprint 15 November 2017
- © 2018 Society for Endocrinology
