# Targeting MCPyV oncogene transcription to suppress tumorigenesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $353,134

## Abstract

Project Summary
Merkel cell polyomavirus (MCPyV) is a ubiquitous skin infection that can cause Merkel cell carcinoma
(MCC), a highly aggressive form of skin cancer. Immune suppression is one of the most important risk
factors for developing MCPyV-associated MCC. MCPyV has a far greater chance to induce cancer
development among immunocompromised individuals, including HIV-infected patients. However, both
the MCPyV life cycle and oncogenic mechanisms remain poorly understood. The incidence of MCC
has tripled over the past twenty years, but effective treatments are lacking. Therefore, a better
understanding of the MCPyV life cycle and oncogenic mechanisms is needed for developing more
effective treatments. In MCPyV-infected cells, the early promoter (EP) supports the transcription of
early genes and plays a critical role in maintaining persistent infection. In the majority of MCCs,
MCPyV DNA is clonally integrated into the cancer genome, where the EP drives the expression of
viral oncogenes, large and small T antigens, to promote MCC tumor growth. MCPyV EP transcription
therefore is also critical for supporting MCC oncogenesis. However, very little is known about the
mechanisms that regulate MCPyV EP during either MCPyV infection or MCC development. This gap
in our knowledge is largely because, until recently, the cellular tropism of MCPyV was unknown and
there was a lack of a biologically relevant culture system for studying MCPyV. We recently identified
human dermal fibroblast (HDF) as a natural host cell for MCPyV infection. We found that MCPyV
entry is a promiscuous process, whereas its transcription is the key determinant for MCPyV host cell
tropism, persistent infection, and oncogenic potential. Building on the in vitro and ex vivo infection
models developed in our recent studies, we propose to discover the epigenetic mechanisms (Aim 1)
as well as host cellular factors and cis-acting viral DNA elements (Aim 2) that regulate MCPyV early
gene transcription. We will also apply the recently developed lipid nanoparticle (LNP) technology to
abolish MCPyV oncogene transcription and obliterate MCC tumorigenesis (Aim 3). Our studies will fill
a significant knowledge gap in understanding the mechanisms that regulate MCPyV early
transcription during the viral life cycle and MCC tumorigenic development. Moreover, our investigation
will provide important insights into the virology and oncogenic mechanism of this new human tumor
virus, and identify novel targets for developing better strategies to treat the highly lethal MCC skin
cancers with a rapidly rising incidence. As demonstrated by the success of COVID-19 vaccines, the
highly potent LNPs have shown great promise for therapeutic applications. Therefore, the superb in
vivo delivery power of LNPs affords a viable platform for translating our findings into clinical setting.

## Key facts

- **NIH application ID:** 10880633
- **Project number:** 5R01CA284690-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jianxin You
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $353,134
- **Award type:** 5
- **Project period:** 2023-07-03 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880633

## Citation

> US National Institutes of Health, RePORTER application 10880633, Targeting MCPyV oncogene transcription to suppress tumorigenesis (5R01CA284690-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10880633. Licensed CC0.

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