Department of General Surgery, Kawasaki Medical School, Okayama, Japan.
General Medical Center Research Unit, Kawasaki Medical School, Okayama, Japan.
Cancer Lett. 2024 Apr 28;588:216816. doi: 10.1016/j.canlet.2024.216816. Epub 2024 Mar 16.
Pulmonary large-cell neuroendocrine carcinoma (LCNEC), a disease with poor prognosis, is classified as pulmonary high-grade neuroendocrine carcinoma, along with small-cell lung cancer. However, given its infrequent occurrence, only a limited number of preclinical models have been established. Here, we established three LCNEC tumoroids for long-term culture. Whole-exome sequencing revealed that these tumoroids inherited genetic mutations from their parental tumors; two were classified as small-cell carcinoma (S-LCNEC) and one as non-small cell carcinoma (N-LCNEC). Xenografts from these tumoroids in immunodeficient mice mimicked the pathology of the parent LCNEC, and one reproduced the mixed-tissue types of combined LCNEC with a component of adenocarcinoma. Drug sensitivity tests using these LCNEC tumoroids enabled the evaluation of therapeutic agent efficacy. Based on translational research, we found that a CDK4/6 inhibitor might be effective for N-LCNEC and that Aurora A kinase inhibitors might be suitable for S-LCNEC or LCNEC with MYC amplification. These results highlight the value of preclinical tumoroid models in understanding the pathogenesis of rare cancers and developing treatments. LCNEC showed a high success rate in tumoroid establishment, indicating its potential application in personalized medicine.
肺大细胞神经内分泌癌（LCNEC）是一种预后不良的疾病，与小细胞肺癌一起被归类为肺高级别神经内分泌癌。然而，由于其罕见的发生，只有有限数量的临床前模型被建立。在这里，我们建立了三个用于长期培养的 LCNEC 类器官。全外显子组测序显示，这些类器官从其亲本肿瘤中遗传了基因突变；其中两个被分类为小细胞癌（S-LCNEC），一个为非小细胞癌（N-LCNEC）。这些类器官在免疫缺陷小鼠中的异种移植物模拟了亲本 LCNEC 的病理学，其中一个重现了具有腺癌成分的混合组织类型的联合 LCNEC。使用这些 LCNEC 类器官进行药物敏感性测试可以评估治疗剂的疗效。基于转化研究，我们发现 CDK4/6 抑制剂可能对 N-LCNEC 有效，而 Aurora A 激酶抑制剂可能适合 S-LCNEC 或 MYC 扩增的 LCNEC。这些结果突出了临床前类器官模型在理解罕见癌症发病机制和开发治疗方法方面的价值。LCNEC 在类器官建立方面成功率较高，表明其在个性化医疗方面具有潜在应用。
