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Principal Investigator: Jianxin You
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $362,492
Funding agency: National Cancer Institute
Project Summary
Merkel cell polyomavirus (MCPyV), the most recently discovered tumor virus, can cause a highly
aggressive form of skin cancer called Merkel cell carcinoma (MCC). While the incidence of MCC has
tripled over the past twenty years, there is no effective therapy for metastatic MCCs, highlighting the
need to better understand MCPyV oncogenic mechanism in order to develop more successful
therapies. MCPyV asymptomatically infects most of the human population, but tends to cause MCC in
the elderly and immunocompromised individuals. These observations suggest that host immunity
plays a critical role in controlling MCPyV-induced tumorigenesis. However, very little is known about
the innate immune response elicited by MCPyV. Neither is it clear how a dysregulated immune
system contributes to MCC tumorigenesis. This is largely because MCPyV tropism was previously
unknown and there was a lack of biologically relevant culture system for MCPyV. Recently, we
discovered that human dermal fibroblasts (HDFs) support productive MCPyV infection and
established the first in vitro as well as ex vivo infection models for MCPyV. Using these systems, we
demonstrated that MCPyV infection activates STING-mediated innate immune responses, which in
turn restrict viral amplification and spread. In addition, we discovered that STING is silenced in
MCPyV(+) MCC tumors, revealing that loss of STING function is needed to drive MCC tumorigenesis.
Our studies suggest that disruption of STING function may cause pathologic rampant replication of
MCPyV to promote viral genome integration into the host genome, which is a key event in MCPyV-
driven tumorigenesis. In addition, loss of STING function may allow MCPyV-induced pre-cancerous
cells to circumvent its tumor suppressive effects, thus stimulating cell proliferation and tumorigenesis.
Building on these observations, we hypothesize that STING functions not only as a key antiviral
immune mediator for controlling MCPyV infection but also a prime tumor suppressor that blocks
MCPyV-driven tumorigenesis. To test this hypothesis, we will combine the in vitro and ex vivo MCPyV
infection models with 3D “artificial human skin” reconstructed in mice to examine the impact of STING
innate immune sensing pathways on MCPyV infection (Aim 1) and to determine how disruption of
STING signaling impacts MCPyV-driven MCC tumorigenesis (Aim 2). Through revealing the largely
unknown interplay between MCPyV and the innate immune system, our ultimate goal is to understand
how poorly controlled MCPyV infection leads to MCC development. Identification of immune effectors
that normally restrict MCPyV propagation could also unveil novel strategies for preventing and treating
the devastating MCC cancers.
Terms: <3-D><3-Dimensional><3D><Antimorphic mutation><Architecture><Assay><Award><Bioassay><Biological Assay><Biological Response Modifiers><Biomodulators><CRISPR><CRISPR/Cas system><Cancers><Causality><Cell Communication and Signaling><Cell Culture System><Cell Culture Techniques><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cellular Proliferation><Cellular Transformation><Cellular Tropism><Clustered Regularly Interspaced Short Palindromic Repeats><Cutaneous Neuroendocrine Carcinoma><DNA><Data><Death Rate><Deoxyribonucleic Acid><Dermal><Development><Dominant Negative><Dominant-Negative Mutant><Dominant-Negative Mutation><Elderly><Engineering / Architecture><Epidemiologic Research><Epidemiologic Studies><Epidemiological Studies><Epidemiology Research><Equilibrium><Etiology><Event><Failure><Fibroblasts><Gene Transcription><General Population><General Public><Genes><Genetic Transcription><Genome><Goals><Host Defense Mechanism><Human><IFN><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immune signaling><Immune system><Immunes><Immunity><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Incidence><Individual><Infection><Innate Immune Response><Innate Immune System><Innate Immunity><Interferons><Intracellular Communication and Signaling><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><Mice><Mice Mammals><Mitogenesis><Modeling><Modern Man><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Neuroendocrine Carcinoma of the Skin><Non-Specific Immunity><Nonspecific Immunity><Nucleic Acids><Oncogenesis><Oncogenic><Oncogenic Viruses><Pathologic><Pathway interactions><Pattern><Play><Polyoma><Polyoma Viruses><Polyomavirus><Polyomavirus Infections><Population><Positive Control of Cell Proliferation><Precancerous Cells><Premalignant Cell><Productivity><Proliferating><RNA Expression><Repression><Research><Risk><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Skin><Skin Cancer><Stimulation of Cell Proliferation><Stimulator of Interferon Genes><Supporting Cell><System><Testing><Trabecular Skin Carcinoma><Transcription><Tropism><Tumor Suppressor Proteins><Tumor Viruses><UV carcinogenesis><UV induced carcinogenesis><UV-induced cancer><Viral><Viral Diseases><Viral Genome><Virus><Virus Diseases><Virus Replication><Virus-Related Malignancy><Virus-Related Malignant Neoplasm><Xenograft Model><advanced age><antagonism><antagonist><balance><balance function><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><causation><cell culture><cell cultures><chronic infection><cyclic GMP-AMP synthase/STING><cytokine><developmental><disease causation><driver lesion><driver mutation><effective therapy><effective treatment><epidemiologic investigation><epidemiology study><gene function><geriatric><host response><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunomodulatory biologics><immunoresponse><immunosuppressed><immunosuppressed patient><immunosuppressive activity><immunosuppressive function><immunosuppressive response><innate immune pathways><innate immune sensing><malignancy><malignant skin tumor><metaplastic cell transformation><mortality rate><mortality ratio><multidisciplinary><neoplasm/cancer><new approaches><novel><novel approaches><novel strategies><novel strategy><oncogenic tumor virus><pathogen><pathway><persistent infection><photo-carcinogenesis><photocarcinogenesis><prevent><preventing><senior citizen><sensor><social role><three dimensional><tool><tumor><tumor suppressor><tumorigenesis><ultraviolet carcinogenesis><ultraviolet induced cancer><ultraviolet induced carcinogenesis><viral associated cancer><viral associated malignancy><viral associated malignant neoplasm><viral induced cancer><viral induced malignancy><viral induced malignant neoplasm><viral infection><viral multiplication><viral related cancer><viral related malignancy><viral related malignant neoplasm><viral replication><virus associated cancer><virus associated malignancy><virus associated malignant neoplasm><virus genome><virus induced cancer><virus induced malignancy><virus induced malignant neoplasm><virus infection><virus multiplication><virus related cancer><virus-induced disease><xenograft transplant model><xenotransplant model>