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Principal Investigator: Jianxin You
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $410,686
Funding agency: National Cancer Institute
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 cancers.
Terms: <AIDS associated cancer><AIDS related cancer><AIDS-Related Malignancy><AIDS-Related Malignant Neoplasm><AIDS-associated malignancies><Affect><Automobile Driving><CRISPR><CRISPR/Cas system><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Induction><Cancer-Promoting Gene><Cancers><Carbonate hydro-lyase><Carbonic Anhydrases><Cell Anoxia><Cell Body><Cell Growth in Number><Cell Hypoxia><Cell Multiplication><Cell Proliferation><Cells><Cellular Anoxia><Cellular Hypoxia><Cellular Proliferation><Cellular Transformation><ChIP Sequencing><ChIP-seq><ChIPseq><Clustered Regularly Interspaced Short Palindromic Repeats><Corium><Cutaneous Neuroendocrine Carcinoma><Cutis><DNA><DNA Alteration><DNA Binding><DNA Binding Interaction><DNA Sequence Alteration><DNA bound><DNA mutation><Data><Death Rate><Deoxyribonucleic Acid><Dermis><Development><Disseminated Malignant Neoplasm><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Gene Expression><Gene Transcription><Genes><Genetic Transcription><Genetic mutation><Genome><HIV-Associated Cancer><HIV-associated malignancy><HIV-related malignancy><HIV/AIDS-associated malignancy><HIV/AIDS-related cancer><Hair Follicle><Hair follicle structure><Human><Hypodermis><Hypoxia><Hypoxic><Hypoxic tumor><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Incidence><Infectious Skin Diseases><Knock-out><Knockout><Knowledge><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Mediating><Merkel Cell Tumor><Merkel Cells><Merkel cell cancer><Merkel cell carcinoma><Merkel's Receptor><Messenger RNA><Metabolic><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modeling><Modern Man><Neoplasm Metastasis><Neuroendocrine Carcinoma of the Skin><Oncogenes><Oncogenesis><Oncogenic><Oncogenic Viruses><Organoids><Oxygen Deficiency><Polyoma><Polyoma Viruses><Polyomavirus><Polyomavirus Infections><Proliferating><RNA Expression><Reader><Risk Factors><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Short interfering RNA><Skin><Skin Cancer><Small Interfering RNA><Subcutaneous Tissue><Subcutis><Superficial Fascia><Tela Subcutanea><Testing><Therapeutic Intervention><Trabecular Skin Carcinoma><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transforming Genes><Tumor Cell><Tumor Promotion><Tumor Viruses><Up-Regulation><Upregulation><VEGF><VEGFA><VEGFA gene><VEGFs><Vascular Endothelial Growth Factor A><Vascular Endothelial Growth Factors><Vasculotropin><Viral><Viral Diseases><Viral Genome><Viral Oncogene><Virus><Virus Diseases><Virus Integration><Virus Replication><Xenograft Model><angiogenesis><cancer metastasis><cancer microenvironment><cancer progression><carbonate dehydratase><carcinogenesis><chromatin immunoprecipitation-sequencing><chronic infection><coping><cutaneous infection><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><developmental><driving><epigenetically><genomic alteration><global gene expression><global transcription profile><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><infected skin><insight><intervention therapy><knock-down><knockdown><laser capture microdissection><lipid based nanoparticle><lipid nanoparticle><mRNA><malignancy><malignant skin tumor><metaplastic cell transformation><mortality rate><mortality ratio><nano particle delivery><nanoparticle delivered><nanoparticle delivery><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><novel approaches><novel strategies><novel strategy><oncogenic tumor virus><persistent infection><pressure><prevent><preventing><recruit><response><short interfering RNA delivery><siRNA><siRNA delivery><skin infection><small interfering RNA delivery><spheroids><subdermal tissue><transcriptome><tumor><tumor cell metastasis><tumor growth><tumor hypoxia><tumor microenvironment><tumor progression><tumorigenesis><tumorigenic><viral infection><viral integration><viral multiplication><viral replication><virus genome><virus infection><virus multiplication><virus-induced disease><xenograft transplant model><xenotransplant model>