Background/Objectives: The Germ Cell Theory of cancer posits that human primordial germ cells (hPGCs) are the cells of origin for malignancies. While this theory is well established for germ cell cancers, a germ cell origin for somatic cancers has been largely overlooked despite clinical observations of malignant somatic transformation (MST), wherein germ cell cancers give rise to diverse somatic cancer phenotypes, often without additional mutations. Methods: To test the Germ Cell Theory experimentally in somatic cancer, we established a virus-driven MST model linking hPGC-like cells (hPGCLCs) to Merkel cell polyomavirus (MCPyV)-positive Merkel cell carcinoma (MCC), a highly aggressive somatic cancer with a germ cell cancer-like, low-mutation epigenetic profile. The MCPyV genome was transduced into human induced pluripotent stem cells (hiPSCs) or hPGC-like cells by lentiviral transfection, followed by xenotransplantation. Results: Virus-positive MCC (VP-MCC)-like tumors were consistently induced without additional oncogenic mutations. These tumors recapitulated VP-MCC’s high-grade neuroendocrine carcinoma histology and molecular profiles. DNA methylation analysis revealed near-complete global hypomethylation in VP-MCC-like tumors, matching the unique epigenetic state of late-stage hPGCs. Notably, pluripotent intermediates were neither necessary nor sufficient for MST; transformation required acquisition of a late-hPGC-like epigenetic state. Conclusions: This is the first MST model of a somatic cancer arising through an aberrant germline-to-soma transition. Our findings unify VP-MCC and germ cell cancer biology, challenge mutation- and soma-centric paradigms, and provide a tractable platform to investigate developmental and epigenetic mechanisms of oncogenesis. This MST model supports a unifying germ cell origin for both germ cell and non-germ cell somatic malignancies.
背景/目的：生殖细胞癌理论认为人类原始生殖细胞是恶性肿瘤的起源细胞。尽管该理论在生殖细胞肿瘤领域已得到广泛认可，但体细胞恶性肿瘤的生殖细胞起源却长期被忽视——尽管临床观察发现恶性体细胞转化现象，即生殖细胞肿瘤可衍生出多种体细胞癌表型，且通常不伴随额外突变。方法：为在体细胞癌中实验验证生殖细胞癌理论，我们建立了病毒驱动的恶性体细胞转化模型，将人类原始生殖细胞样细胞与默克尔细胞多瘤病毒阳性默克尔细胞癌相关联——这是一种具有生殖细胞肿瘤样低突变表观遗传特征的高侵袭性体细胞癌。通过慢病毒转导将默克尔细胞多瘤病毒基因组导入人类诱导多能干细胞或原始生殖细胞样细胞，随后进行异种移植。结果：无需额外致癌突变即可持续诱导产生病毒阳性默克尔细胞癌样肿瘤。这些肿瘤重现了病毒阳性默克尔细胞癌的高级别神经内分泌癌组织学特征与分子谱系。DNA甲基化分析显示病毒阳性默克尔细胞癌样肿瘤存在近乎完全的全局低甲基化，与晚期人类原始生殖细胞的独特表观遗传状态相符。值得注意的是，多能性中间态对恶性体细胞转化既非必需也不充分；转化过程需要获得晚期原始生殖细胞样表观遗传状态。结论：本研究首次建立了通过异常生殖系-体细胞转化产生体细胞癌的恶性体细胞转化模型。我们的发现统一了病毒阳性默克尔细胞癌与生殖细胞肿瘤的生物学机制，挑战了以突变和体细胞为中心的肿瘤发生范式，并为研究肿瘤发生的发育与表观遗传机制提供了可操作平台。该恶性体细胞转化模型支持生殖细胞起源理论可统一解释生殖细胞与非生殖细胞来源的体细胞恶性肿瘤。
肿瘤(癌症)患者之家