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Principal Investigator: Jianxin You
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $371,719
Funding agency: National Cancer Institute
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.
Terms: <2019-nCoV vaccine><AIDS Virus><AIDS associated cancer><AIDS related cancer><AIDS-Related Malignancy><AIDS-Related Malignant Neoplasm><AIDS-associated malignancies><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Sites><Bio-Informatics><Bioinformatics><Body Tissues><COVID-19 vaccine><COVID19 vaccine><CRISPR><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas system><CRISPR/Cas9 screen><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Induction><Cancer-Promoting Gene><Cancers><Carcinoma Cell><Cell Body><Cell Death><Cells><Cellular Tropism><ChIP Sequencing><ChIP-seq><ChIPseq><Chemicals><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Combining Site><Cutaneous Neuroendocrine Carcinoma><DNA><Deoxyribonucleic Acid><Dermal><Development><Early Gene Transcriptions><Early Promoters><Elements><Enhancers><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Fibroblasts><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Genetic analyses><Genome><Goals><Guide RNA><HIV><HIV-Associated Cancer><HIV-associated malignancy><HIV-related malignancy><HIV/AIDS-associated malignancy><HIV/AIDS-related cancer><Heterograft><Heterologous Transplantation><Histones><Human><Human Immunodeficiency Viruses><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Situ><In Vitro><Incidence><Individual><Infection><Infectious Skin Diseases><Investigation><Knock-out><Knockout><Knowledge><LAV-HTLV-III><Life Cycle><Life Cycle Stages><Lymphadenopathy-Associated Virus><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Mediating><Merkel Cell Tumor><Merkel Cells><Merkel cell cancer><Merkel cell carcinoma><Merkel's Receptor><Modeling><Modern Man><Modification><Molecular Interaction><Neuroendocrine Carcinoma of the Skin><Nucleosomes><Oncogenes><Oncogenesis><Oncogenic><Oncogenic Viruses><Patients><Physiologic><Physiological><Play><Polyoma><Polyoma Viruses><Polyomavirus><Polyomavirus Infections><Process><Property><Proteomics><Publishing><RNA Expression><Reactive Site><Reader><Reporter><Risk Factors><Role><SARS-CoV-2 vaccine><SARS-CoV2 vaccine><SARS-coronavirus-2 vaccine><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Skin><Skin Cancer><Small T Antigen><Study models><System><Technology><Therapeutic><Tissues><Trabecular Skin Carcinoma><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Genes><Translating><Tropism><Tumor Viruses><Viral><Viral Diseases><Viral Oncogene><Virus><Virus Diseases><Virus-HIV><Xenograft><Xenograft procedure><Xenotransplantation><cancer cell genome><cancer genome><carcinogenesis><cell type><chromatin immunoprecipitation-sequencing><chronic infection><clustered regularly interspaced short palindromic repeats screen><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cutaneous infection><developmental><driving><effective therapy><effective treatment><epigenetically><experiment><experimental research><experimental study><experiments><gRNA><genetic analysis><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><infected skin><inhibitor><insight><laser capture microdissection><life course><lipid based nanoparticle><lipid nanoparticle><malignancy><malignant skin tumor><mortality><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><necrocytosis><neoplasm/cancer><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><oncogenic tumor virus><permissiveness><persistent infection><prevent><preventing><recruit><screening><screenings><skin infection><social role><success><tool><transcription factor><tumor genome><tumor growth><tumorigenesis><tumorigenic><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine for novel coronavirus><viral DNA><viral infection><virology><virus DNA><virus development><virus infection><virus-induced disease><xeno-transplant><xeno-transplantation>