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

Harold, A. et al. (2019) Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition. Proceedings of the National Academy of Sciences of the United States of America, 116(40), pp. 20104-20114. (doi: 10.1073/pnas.1907154116) (PMID:31527246) (PMCID:PMC6778204)

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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.

Item Type:Articles
Additional Information:M.S. was supported by the Hillman Foundation, Pennsylvania Tobacco Settlement Grant P50CA121973, the University of Pittsburgh Skin Cancer Specialized Program of Research Excellence (SPORE), and National Institutes of Health Cancer Center Support Grant P30 CA047904. E.E. was supported by the Tisch Cancer Institute under P30 Cancer Support Grant and the Irma T. Hirschl Career Scientist Award of the Irma T. Hirschl Trust. J.C.B. was supported by the European Union’s Seventh Framework Program (FP7-HEALTH-2011-two-stage, Immune Modulating Strategies for Treatment of Merkel Cell Carcinoma [IMMOMEC]) under Grant Agreement 277775 (granted to J.C.B.); J.C.B. was supported by the German Cancer Consortium (DKTK L441).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hachisuka, Dr Junichi
Authors: Harold, A., Amako, Y., Hachisuka, J., Bai, Y., Li, M. Y., Kubat, L., Gravemeyer, J., Franks, J., Gibbs, J. R., Park, H. J., Ezhkova, E., Becker, J. C., and Shuda, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
Published Online:16 September 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Proceedings of the National Academy of Sciences of the United States of America 116(40): 20104-20114
Publisher Policy:Reproduced under a Creative Commons License

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