PO.TB04.06 · 肿瘤生物学
开发神经内分泌癌PDX模型的可行性与挑战
Feasibility and challenges of developing PDX models of neuroendocrine cancers
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
神经内分泌肿瘤（NEN）是一类具有神经元和激素分泌特征的异质性癌症家族。NEN分为生长缓慢的高分化神经内分泌肿瘤（NET）和生长迅速的低分化神经内分泌癌（NEC）。在过去二十年间，NEN的发病率和患病率稳步上升。然而，可用于治愈这些复杂疾病的有效治疗选择却很少。主要瓶颈与缺乏用于疗法测试的临床前NEN模型有关。NET患者来源类器官或球体模型的最新进展显著改善并加速了药物发现流程。此外，多个研究团队也成功报道了开发NEC患者来源异种移植瘤（PDX）模型的努力。然而，开发NET PDX模型的努力在很大程度上仍未成功。我们团队旨在优先开发新型NET PDX模型。我们将从50例患者肿瘤样本（源自小肠和胰腺NET，即sbNET和pNET）中分离的肿瘤细胞皮下植入NOD scid IL2R gamma null（NSG）小鼠。9次移植在3-6个月内产生了可检测的肿瘤。其中，2组小鼠携带自发形成的、无神经内分泌特征的小鼠肿瘤，7组小鼠携带经短串联重复分析确认与原始患者NET样本匹配的人类肿瘤样本。7个PDX肿瘤中有6个在植入肿瘤细胞后4-6个月时直径小于5 mm。尽管这些肿瘤体积较小，但它们重现了NET特征，并表达突触素（SYP）、嗜铬粒蛋白A（CgA）或生长抑素受体2（SSTR2）等NET标志物，Ki67染色在不到25%的肿瘤细胞中呈阳性。一个pNET PDX模型在植入肿瘤细胞后3个月时产生了直径超过10 mm的大肿瘤。有趣的是，这些大肿瘤对SYP、CgA或SSTR2染色呈阴性，并表现出升高的Ki67水平（超过35%）。这些PDX模型突变格局的分析正在进行中，将揭示阻碍NET PDX模型开发的关键遗传调控因子的相关见解。总体而言，这些发现凸显了开发NET PDX的可行性与挑战。
查看英文原文 English abstract
Neuroendocrine neoplasms (NENs) are a family of heterogenous cancers with neuronal and hormone-secreting features. NENs are subdivided into slow growing well-differentiated neuroendocrine tumors (NETs) and rapidly growing poorly differentiated neuroendocrine carcinomas (NECs). The incidence and prevalence of NENs have been steadily rising over the last twenty years. Yet, few effective therapeutic options are available for curing these complex diseases. The main bottleneck has been linked to the lack of preclinical NEN models for therapy testing. Recent advances in NET patient-derived organoid or spheroid models have significantly improved and contributed to accelerating the drug discovery pipeline. In addition, efforts in developing patient-derived xenograft (PDX) models of NECs have also been successfully reported by several research groups. However, efforts to develop PDX models of NETs remained largely unsuccessful. Our group aimed to prioritize the development of novel NET PDX models. We performed subcutaneous implantation of tumor cells isolated from 50 patient tumor samples from small bowel and pancreatic NETs (sbNETs and pNETs) in NOD scid IL2R gamma null (NSG) mice. Nine engraftments produced detectable tumors within 3-6 months. Of these, 2 sets of mice harbored spontaneously developed mouse tumors with no neuroendocrine feature, and 7 sets of mice harbored human tumor samples confirmed by short tandem repeat analyses to match with the original patient NET samples. Six of the 7 PDX tumors measured less than 5 mm in diameter at 4-6 months post-tumor cell implantation. Although these tumors were small, they recapitulated NET features and expressed NET markers such as synaptophysin (SYP), chromogranin A (CgA), or somatostatin receptor 2 (SSTR2), and have Ki67 staining in less than 25% of the tumor cells. One pNET PDX model yielded large tumors measuring over 10 mm in diameter at 3 months post-tumor cell implantation. Interestingly, these large tumors stained negative for SYP, CgA, or SSTR2, and displayed elevated Ki67 levels (over 35%). Analyses of the mutational landscape of these PDX models are underway and will reveal insights into key genetic regulators that hinder the development of NET PDX models. Overall, these findings highlight both the feasibility and challenges of developing NET PDX.
利益披露 Disclosure
C. A. Morgan, None..
A. A. Peterson, None..
P. H. Ear, None.