Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [thyroid]

Transcriptome profiling of rat NETs 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 versus 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 associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive/metastatic MTC, exploitable for translational studies of this aggressive and often incurable cancer.对不同p27剂量的大鼠神经内分泌肿瘤（neuroendocrine tumors, NETs）开展转录组谱分析，揭示了p27对基因表达的组织特异性、剂量依赖性调控效应。在p27+/mut大鼠中，甲状腺肿瘤会进展为侵袭性及转移性甲状腺髓样癌（medullary thyroid carcinomas, MTCs），并伴随降钙素水平升高，这与人类患者的表型一致。对比来自p27+/mut大鼠的晚期与早期MTC的表达特征，可筛选出潜在参与肿瘤侵袭性调控的基因。对其中部分基因的表达在人类MTC中进行了验证，发现其与侵袭性RET-M918T阳性肿瘤存在关联。综上，MENX大鼠的p27单倍体剂量不足现象，揭示了一种新型且具有代表性的侵袭/转移性MTC模型，可用于这类恶性程度高且常难以治愈的癌症的转化研究。