Possible Rotation Projects:
- Mechanisms by which MCV small T antigen coordinates the activation of viral DNA replication, viral late gene transcription, and viral late transcript maturation.
- Epigenetic control of the Merkel cell phenotype of MCC cancer cells by CBP/p300
Training Technologies Used:
- Use recombinant MCV to study persistent infection.
- Gain and loss of functional approach with lentivirus-based cDNA expression, shRNA knockdown, and CRISPR-Cas9 knockout
- Unbiased genetic approach with NGS, such as ATAC-Seq, Cut&Run, and RNA-seq
- Proteomic approach: TurboID and tandem affinity purification
- B.S. (Allied Health Science), Tokyo Medical and Dental University (1995)
- Ph.D. (Molecular Virology), Tokyo Medical and Dental University (2002)
Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096-100. Epub 2008/01/19. doi: 10.1126/science.1152586. PubMed PMID: 18202256; PMCID: PMC2740911.
Velasquez C, Amako Y, Harold A, Toptan T, Chang Y, Shuda M. Characterization of a Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cell Line CVG-1. Front Microbiol. 2018;9:713. Epub 2018/04/27. doi: 10.3389/fmicb.2018.00713. PubMed PMID: 29696010; PMCID: PMC5905237.
Harold A, Amako Y, Hachisuka J, Bai Y, Li MY, Kubat L, Gravemeyer J, Franks J, Gibbs JR, Park HJ, Ezhkova E, Becker JC, Shuda M. Conversion of Sox2-dependent Merkel cell carcinoma to a differentiated neuron-like phenotype by T antigen inhibition. Proc Natl Acad Sci U S A. 2019;116(40):20104-14. Epub 2019/09/19. doi: 10.1073/pnas.1907154116. PubMed PMID: 31527246; PMCID: PMC6778204.
Abere B, Zhou H, Shuda M, Stolz DB, Rapchak K, Moore PS, Chang Y. Replication Kinetics for a Reporter Merkel Cell Polyomavirus. Viruses. 2022;14(3). Epub 2022/03/27. doi: 10.3390/v14030473. PubMed PMID: 35336880; PMCID: PMC8950423.
Rapchak K, Yagobian SD, Moore J, Khattri M, Shuda M. Merkel cell polyomavirus small T antigen is a viral transcription activator that is essential for viral genome maintenance. PLoS Pathog. 2022;18(12):e1011039. Epub 2022/12/28. doi: 10.1371/journal.ppat.1011039. PubMed PMID: 36574443; PMCID: PMC9829177.
Khattri M, Amako Y, Gibbs JR, Collura JL, Arora R, Harold A, Li MY, Harms PW, Ezhkova E, Shuda M. Methyltransferase-independent function of enhancer of zeste homologue 2 maintains tumorigenicity induced by human oncogenic papillomavirus and polyomavirus. Tumour Virus Res. 2023;16:200264. Epub 2023/05/28. doi: 10.1016/j.tvr.2023.200264. PubMed PMID: 37244352.
Weber M, Nguyen MB, Li MY, Flora P, Shuda M, Ezhkova E. Merkel cell polyomavirus T-antigen-mediated reprogramming in adult Merkel cell progenitors. J Invest Dermatol. 2023. Epub 2023/06/01. doi: 10.1016/j.jid.2023.04.031. PubMed PMID: 37257637.
Gupta P*, Venuti A, Savoldy M, Harold A, Zito FA, Taverniti V, Romero-Medina MC, Galati L, Sirand C, Shahzad N, Shuda M*, Gheit T*, Accardi R, Tommasino M. Merkel Cell Polyomavirus targets SET/PP2A complex to promote cellular proliferation and migration. Virology 2024;597:110143 doi: 10.1016/j.virol.2024.110143. PubMed PMID: 38917692. *Equal corresponding author
Shuda M. Tumor virus-induced lineage survival circuit drives Merkel cell carcinogenesis. J Clin Invest. 2025;135(24). Epub 20251215. doi: 10.1172/JCI200581. PubMed PMID: 41392986.
Collura JL, Lei KC, Chandra M, Kervarrec T, Park HJ, Dalkoohi M, Becker JC, Chang Y, Moore PS, Shuda M. Pharmacologic reversion of Merkel cell carcinoma via CBP/p300 inhibition. Proc Natl Acad Sci U S A. 2025;122(52):e2516667122. Epub 20251224. doi: 10.1073/pnas.2516667122. PubMed PMID: 41439710.
Tumor virus research has provided a wealth of information for cancer biology. Polyomaviruses, small DNA tumor viruses that efficiently transform normal healthy cells into cancer cells, have been central to understanding the basic mechanisms of cancer cell transformation. Studies on the animal polyomavirus SV40, for example, led to the discovery of tumor suppressor protein p53 and uncovered the functions of tumor suppressor protein pRb in cell cycle regulation. My laboratory studies Merkel cell polyomavirus (MCV), the first human oncogenic polyomavirus identified from human Merkel cell carcinoma (MCC) and high-risk human papillomavirus (HPV), a causal agent of cervical cancers and head and neck squamous cell cancers (SCC).
Our research is based on two pillars: Molecular Virology, to identify the mechanism of persistent infection, and Cancer Biology, to understand how viral oncogenes exploit cellular signaling for carcinogenesis. The molecular virology project leads toward persistence mechanisms of MCV, with a focus on the viral small T antigen protein (ST), which is dispensable for viral DNA replication initiation, yet critical for promoting viral DNA replication and required for viral structural protein gene (or late gene) induction. We seek to understand how ST induces viral late gene expression to progress virus lifecycle from replication to progeny virus production. Our cancer biology project focuses on the host proteins that mediate “oncogenic addiction of viral cancers to viral oncogenes” in MCV-positive cancers and HPV-positive cancers. We recently identified epigenetic enzymes, CBP/p300 histone acetyltransferases, as a critical driver of tumorigenesis and Merkel cell phenotype, showing that small molecule inhibition of CBP/p300 reverted MCC cancer phenotype to quiescent neuronal cells, abolishing Merkel cell markers. We are keen on identifying how virus oncoproteins promote a phenotype associated with Merkel cell lineage during carcinogenesis.
