High-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis

dc.creatorNaipauer, Julian
dc.creatorSalyakina, Daria
dc.creatorJourno, Guy
dc.creatorRosario, Santas
dc.creatorWilliams, Sion
dc.creatorAbba, Martín Carlos
dc.creatorShamay, Meir
dc.creatorMesri, Enrique A.
dc.date2020
dc.date2020-10-29T13:51:24Z
dc.date.accessioned2023-07-14T22:44:56Z
dc.date.available2023-07-14T22:44:56Z
dc.identifierhttp://sedici.unlp.edu.ar/handle/10915/107926
dc.identifierhttp://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7357787&blobtype=pdf
dc.identifierhttps://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008589
dc.identifierissn:1553-7374
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/7448057
dc.descriptionKaposi’s sarcoma (KS), is an AIDS-associated neoplasm caused by the KS herpesvirus (KSHV/ HHV-8). KSHV-induced sarcomagenesis is the consequence of oncogenic viral gene expression as well as host genetic and epigenetic alterations. Although KSHV is found in all KS-lesions, the percentage of KSHV-infected (LANA+) spindle-cells of the lesion is variable, suggesting the existence of KS-spindle cells that have lost KSHV and proliferate autonomously or via paracrine mechanisms. A mouse model of KSHVBac36-driven tumorigenesis allowed us to induce KSHV-episome loss before and after tumor development. Although infected cells that lose the KSHV-episome prior to tumor formation lose their tumorigenicity, explanted tumor cells that lost the KSHV-episome remained tumorigenic. This pointed to the existence of virally-induced irreversible oncogenic alterations occurring during KSHV tumorigenesis supporting the possibility of hit and run viral-sarcomagenesis. RNA-sequencing and CpG-methylation analysis were performed on KSHV-positive and KSHV-negative tumors that developed following KSHV-episome loss from explanted tumor cells. When KSHV-positive cells form KSHV-driven tumors, along with viral-gene upregulation there is a tendency for hypo-methylation in genes from oncogenic and differentiation pathways. In contrast, KSHV-negative tumors formed after KSHV-episome loss, show a tendency towards gene hyper-methylation when compared to KSHV-positive tumors. Regarding occurrence of host-mutations, we found the same set of innate-immunity related mutations undetected in KSHV-infected cells but present in all KSHV-positive tumors occurring en exactly the same position, indicating that pre-existing host mutations that provide an <i>in vivo</i> growth advantage are clonally-selected and contribute to KSHV-tumorigenesis. In addition, KSHV-negative tumors display <i>de novo</i> mutations related to cell proliferation that, together with the PDGFRAD842V and other proposed mechanism, could be responsible for driving tumorigenesis in the absence of KSHV-episomes. KSHV-induced irreversible genetic and epigenetic oncogenic alterations support the possibility of “hit and run” KSHVsarcomagenesis and point to the existence of selectable KSHV-induced host mutations that may impact AIDS-KS treatment.
dc.descriptionFacultad de Ciencias Médicas
dc.descriptionCentro de Investigaciones Inmunológicas Básicas y Aplicadas
dc.formatapplication/pdf
dc.languageen
dc.rightshttp://creativecommons.org/licenses/by/4.0/
dc.rightsCreative Commons Attribution 4.0 International (CC BY 4.0)
dc.subjectMedicina
dc.subjectcancers and neoplasms
dc.subjectDNA methylation
dc.subjectcarcinogenesis
dc.subjectmalignant tumors
dc.subjectepigenetics
dc.subjectviral gene expression
dc.subjectvirus effects on host gene expression
dc.subjectmammalian genomics
dc.titleHigh-throughput sequencing analysis of a "hit and run" cell and animal model of KSHV tumorigenesis
dc.typeArticulo
dc.typeArticulo


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