Abstract 5170: A xenograft mouse model of virus-positive Merkel cell carcinoma directly links germ cell theory to somatic cancer

Abstract While mutation theory has dominated the somatic cancer arena for decades, germ cell theory has been the necessary alternative for germ cell tumors (GCTs) with their unique (epi)genomic profiles. However, all cancers are unified by a set of hallmarks and the paradigm division between somatic versus GCTs has been challenged by accumulating paradoxes. Merkel cell polyomavirus (McPyv) positive Merkel cell carcinoma (MCC), a very rare and highly malignant skin cancer, is one such striking paradox contradicting the cancer mutation theory. MCC is a small cell neuroendocrine carcinoma (SCNC) with 80% containing McPyv, a tiny ubiquitous DNA virus of normal skin flora. In common with GCTs, virus-positive (VP)-MCC exhibits striking genomic stability in dichotomy to its virus-negative counterparts and other SCNCs. Intriguingly, the SCNC phenotype is also the pan-cancer convergent end state of tumor progression/dedifferentiation, implicating closeness to somatic cancer stem cells. It is thus rational to hypothesize VP-MCC being an extra-gonadal GCT with oncovirus driven malignant somatic transformation (MST) in an adult cutaneous niche. GCT research has supported human primordial germ cells (hPGCs) being the cell of origin for GCTs. hPGCs are considered unipotent that cannot form teratomas in adult mice but are readily converted in vitro to pluripotent human embryonic germ cells (hEGCs) that can form teratomas in adult mice, like pluripotent human ESCs (hESCs) or human iPSCs (hiPSCs) which may rarely spontaneously differentiate to hPGCs in vitro. To validate our hypothesis, we performed a mouse study by injecting hPGC-like cells (hPGCLCs) with or without McPyv transfection to NSG mouse flank skin, as well as McPyv transfected hiPSCs and hEGC-like cells (hEGCLCs). We then monitored tumor formation and growth over 4 months. All tumors were analyzed for histology and gene/protein expression by H&E, immunohistochemistry, flow cytometry and/or RT-qPCR. 2 out of 3 mice injected by McPyv transfected hPGCLCs exhibited MST to typical MCC-like tumors from a background of teratoma. All mice injected with McPyv transfected hiPSCs or hEGCLCs formed teratomas as expected, but only tumors derived from very high number hiPSC injections showed MST to atypical MCC-like tumors. Our findings thus demonstrated McPyv transfection enabled MST to MCC-like tumors from hPGCLCs and high dose hESCs. Per literature search, this is the first MST model to directly link germ cell theory to somatic cancer, with its simplicity to enable easy tractability of molecular events. Disclaimer: The opinions and assertions expressed herein are those of the author(s) and do not reflect the official policy or position of the Uniformed Services University of the Health Sciences or the Department of Defense. Citation Format: Sara Contente, Sarah Rahman, Wendy Yang. A xenograft mouse model of virus-positive Merkel cell carcinoma directly links germ cell theory to somatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5170.