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

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)20104-20114
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number40
DOIs
StatePublished - 1 Oct 2019

Keywords

  • Merkel cell carcinoma
  • Merkel cell polyomavirus
  • Phenotypic conversion
  • Sox2 | Atoh1

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