yang, w.; contente, s.; rahman, s.

The Germ Cell Theory, grounded in developmental biology, has enabled significant advances in understanding and treating germ cell tumors (GCTs), whereas somatic cancer research, dominated by the Somatic Mutation Theory (SMT), has stagnated and demands a paradigm shift. Accumulating evidence challenges the traditional separation between GCTs and somatic cancers. Polyomavirus-positive Merkel cell carcinoma (VP-MCC), an aggressive somatic cancer with exceptional genomic stability resembling GCTs yet paradoxical to SMT, suggested the potential for linking Germ Cell Theory to somatic oncogenesis. By inducing VP-MCC-like tumors from polyomavirus-transfected human primeval stem cells in mice, we directly established this link. This novel malignant somatic transformation model offers an unprecedented platform to dissect the molecular underpinning of VP-MCC carcinogenesis and advocates a developmental biology approach for somatic cancer research.