KSHV-infected endothelial cells expand and up-regulate angiogenic pathways and CXCR4 in patient-derived Kaposi sarcoma models
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE290108 | GEO | 2026/07/01
REPOSITORIES: GEO
Similar Datasets
Project description:Kaposi sarcoma (KS) is defined by hyperangiogenesis driven by Kaposi sarcoma herpesvirus (KSHV) infected endothelial cells. The exploration of novel therapies is hampered by the lack of a patient-derived preclinical animal model. Here, we characterize patient-derived KS xenografts (PDXs) in immunodeficient NOD/SCID/gamma (NSG) mice. Thirteen cutaneous KS biopsies were subcutaneously implanted into NSG or NOG mice transgenic for human IL-6. Immunohistochemistry staining for KSHV LANA revealed that infected endothelial cells were maintained for long periods in recipient NSG. LANA+ human endothelial cells increased by a mean 4.3-fold in fifteen PDX compared to respective input biopsies, regardless of numerous implantation variables and clinical history of patient volunteers. The Ki-67 proliferation marker overlapped with LANA+ cells, consistent with virus-driven cell expansion. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. In addition, the expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with a notable enrichment in pathways associated with angiogenesis, development of endothelium, lipid transport and cell growth. Spatial analysis revealed that fibroblasts in the KS tumor microenvironment may be one source of CXCL12 signaling to CXCR4 that was upregulated in KS tumor regions. Taken together, the reproducible expansion of KSHV-infected endothelial cells across PDX from multiple donors and the recapitulation of a KS tumor gene signature, discovers new biology and supports the application of patient-derived cutaneous KS xenografts as a pre-clinical model to test novel therapies.
2026-07-01 | GSE277153 | GEO
Project description:Kaposi’s Sarcoma (KS) is a heterogenous, multifocal vascular malignancy caused by the human herpesvirus 8 (HHV8), also known as Kaposi’s Sarcoma-Associated Herpesvirus (KSHV). Here, we show that KS lesions express iNOS/NOS2 broadly throughout KS lesions, with enrichment in LANA positive spindle cells. The iNOS byproduct 3-nitrotyrosine is also enriched in LANA positive tumor cells and colocalizes with a fraction of LANA-nuclear bodies. We show that iNOS is highly expressed in the L1T3 tumor model of KS. iNOS expression correlated with KSHV lytic cycle gene expression, which was elevated in late-stage tumors (>4 weeks) but to a lesser degree in early stage (1 week) xenografts. Further, we show that L1T3 tumor growth is sensitive to an inhibitor of nitric oxide, L-NMMA. These finding suggest that iNOS is expressed in KSHV infected endothelial-transformed tumor cells in KS, that iNOS expression depends on tumor microenvironment stress conditions, and that iNOS enzymatic activity contributes to KS tumor growth.
2023-07-14 | GSE222527 | GEO
Project description:KSHV-infected endothelial cells expand and up-regulate angiogenic pathways and CXCR4 in patient-derived Kaposi sarcoma models
| PRJNA1160880 | ENA
Project description:KSHV-infected endothelial cells expand and up-regulate angiogenic pathways and CXCR4 in patient-derived Kaposi sarcoma models
| PRJNA1226213 | ENA
Project description:The Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies.
2016-05-31 | GSE69067 | GEO
Project description:The Kaposiâs Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposiâs Sarcoma (KS), which preferentially arise in immunocompromised patients but lack of effective therapeutic options. We have previously shown that KSHV or viral protein LANA can upregulate the glycoprotein CD147 (Emmprin) to induce primary endothelial cell invasiveness, which also requires PI3K/Akt and MAPK activation of VEGF production. In the current study, we first time identify the global network controlled by CD147 in KSHV-infected endothelial cells using Illumina microarray analysis. Among these downstream genes, ADAMTS1 and 9, two specific metalloproteases are strongly expressed in AIDS-KS tissues and contributed to KSHV-infected cell invasiveness through regulation of related cytokines production and respective receptors expression. By using a nude mice KS-like model, we found that targeting CD147 and downstream ADAMTSs proteins significantly suppressed KSHV-related tumorigenesis in vivo, which is potentially through impairing extracellular matrix (ECM) formation in tumor microenvironment. Taken together, we think that targeting CD147 and related proteins may represent a promising therapeutic strategy against KSHV-related malignancies. HUVEC cells were infected by KSHV or transduced by a CD147 recombinant adenoviral vector and the gene expression signature was compared to respective controls
2016-05-31 | E-GEOD-69067 | biostudies-arrayexpress
Project description:Kaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.
2019-12-12 | GSE141866 | GEO
Project description:Kaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.
2019-12-12 | GSE141844 | GEO
Project description:Gene expression profiling of three PEL cell lines compare to three Burkitt's lymphoma lines to figure out the changed genes under KSHV latent infection. Gene expression profiling of two time points on TIVE cells after infection by KSHV compare to TIVE cell without infection by KSHV to figure out the changed genes on TIVE cell under latent infection of KSHV. Gene expression profiling of four time points after inducing recombinant LANA protein expression when compare to no inducing BJAB/Tet-On/LANA cells to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression. Gene expression profiling of three time points after inducing recombinant LANA protein expression when compare to no inducing Jurkat/Tet-On/LANA cell line to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression. Gene expression profiling of two time points after inducing recombinant LANA protein expression when compare to no inducing 293/Tet-On/LANA cell line to figure out the changed genes under the latency-associate nuclear antigen (LANA) of KSHV expression. Keywords = TIVE Keywords = KSHV Keywords = LANA Keywords = PEL Keywords = BJAB Keywords = 293 Keywords = Jurkat Keywords: other
2004-10-27 | GSE1880 | GEO
Project description:Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and two human lymphoproliferative diseases: primary effusion lymphoma and AIDS-related multicentric Castleman's disease. KSHV latency-associated nuclear antigen (LANA) is expressed in KSHV-infected cancer cells and is responsible for maintaining viral genomes in infected cells. Thus, LANA is an attractive target for therapeutic intervention for KSHV-associated diseases. Here, we devised a gene therapy vector using the adeno-associated virus (AAV), which capitalizes the LANA's function to tether terminal repeat (TR) containing circular genome in latently infected cells and the TR's enhancer function for KSHV inducible gene promoters. By including two TR copies with a lytic inducible gene promoter (TR2-Orip), we generated an AAV vector, which expresses an engineered thymidine kinase (TK) selectively in KSHV-infected cells. Ganciclovir (GCV), an anti-herpesvirus drug, effectively eradicated multiple KSHV-infected cells that include iPSC derived epithelial colony forming cells, but not non-KSHV-infected counterparts in the presence of AAV8-TR2-Orip-TK. In addition, AAV8-TR2-Orip-TK prevents KSHV virion production from reactivated cells, hence spreading KSHV infections from reactivated cells. Anti-cancer drugs, known to reactivate KSHV, stimulated TK expression from the vector and, therefore, synergized with AAV8 TR2-Orip-TK to induce KSHV-infected cancer cell death. Finally, the AAV8-TR2-Orip-TK with GCV completely diminished KSHV-infected cancer cells in the xenograft tumor model. Our new cancer gene therapy should augment the current clinical protocol for KS.
2025-02-19 | GSE289947 | GEO