Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition

• DOI: 10.1073/pnas.1907154116
• Publication Date: 2019-09-17T00:35:45Z
• Authors: Alexis Harold; Yutaka Amako; Junichi Hachisuka; Yulong Bai; Meng Yen Li; Linda Kubat; Jan Gravemeyer; Jonathan Franks; Julia R. Gibbs; Hyun Jung Park; Elena Ezhkova; Jürgen C. Becker; Masahiro Shuda
• Keywords: Merkel cell polyomavirus; Merkel cell

Viral cancers show oncogene addiction to viral oncoproteins, which are required for survival and proliferation of the dedifferentiated cancer cell. Human Merkel cell carcinomas (MCCs) that harbor a clonally integrated polyomavirus (MCV) genome have low mutation burden require T antigen expression tumor growth. Here, we showed MCV + MCC cells cocultured with keratinocytes undergo neuron-like differentiation neurite outgrowth, secretory vesicle accumulation, generation sodium-dependent action potentials, hallmarks neuronal lineage. Cocultured essential induction phenotype. Keratinocyte-conditioned medium was insufficient induce this Single-cell RNA sequencing revealed knockdown inhibited cycle gene reduced key lineage/MCC marker genes, including HES6 , SOX2 ATOH1 KRT20 . Of these, directly Sox2 Atoh1 expression. large up-regulated through its retinoblastoma protein-inhibition domain, in turn activated The MCCs mimicked by inducing growth arrest differentiation. These results Sox2-dependent conversion an undifferentiated, aggressive differentiated phenotype suggest ontology arises from precursor.