# Project 3: Skin hypoxia, MCPyV infection, and MCC tumorigenesis

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $410,686

## Abstract

Project Abstract
Merkel cell carcinoma (MCC) is one of the most aggressive skin cancers. Clonal integration of Merkel cell
polyomavirus (MCPyV) genome into the host DNA has been observed in ~80% of MCCs, and represents a key
causal factor for MCC development. LT and sT encoded by MCPyV genome have been shown to support not
only viral replication but also MCPyV-induced tumorigenesis. Immune suppression is another important risk
factor for the development of MCPyV-associated MCC. MCC has a nearly 50% mortality rate. The incidence of
MCC has increased by >95% in the US since 2000. MCC is highly prone to metastasis. The metastatic
cancers are more difficult to treat and can often be fatal. Thus, there is a need to better understand the
oncogenic mechanisms of MCPyV and MCC in order to develop new strategies to prevent and treat this highly
lethal skin cancer. MCC tumors are usually detected in the human dermis, which maintain a hypoxic
microenvironment. Hypoxia supports tumor progression partly by driving metabolic adaptation, angiogenesis
and metastasis, through upregulation of hypoxia-regulated genes. Importantly, we found that a large number of
hypoxia genes are highly induced in MCC, suggesting that the hypoxic skin microenvironment represents an
important starting point for MCC progression and metastatic spread. Some of these genes such as carbonic
anhydrase 9 (CA9) and vascular endothelial growth factor A (VEGF-A) are critical for promoting tumor growth
and metastasis. However, how MCPyV infected cells and MCC tumor cells respond to hypoxia and the impact
of hypoxia-regulated gene expression on MCPyV infection and MCC tumorigenesis remain largely unknown.
We showed that MCPyV oncogene LT is associated with epigenetic reader BRD4, which functionally interacts
with HIF-1α, a key regulator of hypoxic responses, to control the transcription of hypoxic genes such as CA9
and VEGF-A. We also found that MCPyV sT can induce hypoxic gene expression. Building on these findings,
we hypothesize that collaborative interactions between MCPyV LT and sT with their host partners, such as
BRD4 and HIF-1α, collectively regulate hypoxia gene expression in MCPyV-infected and MCC origin cells to
promote viral infection and MCC tumorigenesis. In this project, we propose to determine how MCPyV interacts
with the host cells in the hypoxic skin environment (Aim 1), characterize the impact of LT-BRD4-HIF-1α
interaction on hypoxic gene expression in skin cells (Aim 2), and investigate the function of MCPyV oncogenes
in controlling MCC hypoxic reprograming and the impact on MCC tumorigenesis (Aim 3). These results will fill
the gap in our understanding of hypoxic response mechanism in MCPyV-infected cells and associated MCC.
Our study may provide new insights into viral and cellular factors that support hypoxia-mediated metabolic
reprogramming during MCPyV infection and MCC oncogenic development, revealing new strategies to
improve therapeutic intervention of MCPyV-induced ...

## Key facts

- **NIH application ID:** 10914922
- **Project number:** 5P01CA281867-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jianxin You
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,686
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914922

## Citation

> US National Institutes of Health, RePORTER application 10914922, Project 3: Skin hypoxia, MCPyV infection, and MCC tumorigenesis (5P01CA281867-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10914922. Licensed CC0.

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