{"doi":"10.1101/2024.09.27.615429","title":"Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Kaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive for\n                  <jats:italic>de novo</jats:italic>\n                  KSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary</jats:title>\n                  <jats:p>Tumor virus-driven expansion of endothelial cells with a transcriptional signature of Kaposi sarcoma in a large cohort of patient-derived xenografts provides a platform to discover cell communications within the tumor microenvironment.</jats:p>\n                </jats:sec>","journal":null,"year":null,"id":645975,"datarank":0.24141568686511508,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.0,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":250444,"name":"Zoë Weaver Ohler","orcid":"0000-0002-6287-2504","position":1,"is_corresponding":false},{"id":266096,"name":"Amanda Day","orcid":"0000-0002-4456-8883","position":2,"is_corresponding":false},{"id":658614,"name":"Laura Bassel","orcid":"0000-0003-1684-6839","position":3,"is_corresponding":false},{"id":1682228,"name":"Anna Grosskopf","orcid":null,"position":4,"is_corresponding":false},{"id":598521,"name":"Bahman Afsari","orcid":"0000-0001-8717-7199","position":5,"is_corresponding":false},{"id":486265,"name":"Takanobu Tagawa","orcid":"0000-0001-8637-2996","position":6,"is_corresponding":false},{"id":964629,"name":"Wendi Custer","orcid":null,"position":7,"is_corresponding":false},{"id":560389,"name":"Ralph Mangusan","orcid":"0000-0003-4775-8655","position":8,"is_corresponding":false},{"id":334813,"name":"Kathryn Lurain","orcid":"0000-0002-5794-7292","position":9,"is_corresponding":false},{"id":181815,"name":"Robert Yarchoan","orcid":null,"position":10,"is_corresponding":false},{"id":1682229,"name":"Joseph Ziegelbauer","orcid":null,"position":11,"is_corresponding":false},{"id":334815,"name":"Ramya Ramaswami","orcid":"0000-0001-5709-4675","position":12,"is_corresponding":false},{"id":433935,"name":"Laurie T. Krug","orcid":"0000-0002-9648-522X","position":13,"is_corresponding":false},{"id":120958,"name":"Xiaofan Li","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Kaposi sarcoma (KS) is defined by aberrant angiogenesis driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells with endothelial characteristics. KS research is hindered by rapid loss of KSHV infection upon explant culture of tumor cells. Here, we establish patient-derived KS xenografts (PDXs) upon orthotopic implantation of cutaneous KS biopsies in immunodeficient mice. KS tumors were maintained in 27/28 PDX until experimental endpoint, up to 272 days in the first passage of recipient mice. KSHV latency associated nuclear antigen (LANA)+ endothelial cell density increased by a mean 4.3-fold in 14/15 PDX analyzed by IHC at passage 1 compared to respective input biopsies, regardless of implantation variables and clinical features of patients. The Ki-67 proliferation marker colocalized with LANA more frequently in PDXs. Spatial transcriptome analysis revealed increased expression of viral transcripts from latent and lytic gene classes in the PDX. The expanded KSHV+ regions of the PDX maintained signature gene expression of KS tumors, with enrichment in pathways associated with angiogenesis and endothelium development. Cells with characteristics of tumor-associated fibroblasts derived from PDX were propagated for 15 passages. These fibroblast-like cells were permissive for\n                  <jats:italic>de novo</jats:italic>\n                  KSHV infection, and one lineage produced CXCL12, a cancer-promoting chemokine. Spatial analysis revealed that fibroblasts are a likely source of CXCL12 signaling to CXCR4 that was upregulated in KS regions. The reproducible expansion of KSHV-infected endothelial cells in PDX from multiple donors and recapitulation of a KS tumor gene signature supports the application of patient-derived KS mouse models for studies of pathogenesis and novel therapies.\n                </jats:p>\n                <jats:sec>\n                  <jats:title>One Sentence Summary</jats:title>\n                  <jats:p>Tumor virus-driven expansion of endothelial cells with a transcriptional signature of Kaposi sarcoma in a large cohort of patient-derived xenografts provides a platform to discover cell communications within the tumor microenvironment.</jats:p>\n                </jats:sec>","is_dataset_classified":null,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"39386738","pmcid":null,"openalex_id":"https://openalex.org/W4402939303","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"1ZIABC011953-01","title":"Investigation of viral and host determinants of gammaherpesvirus pathogenesis"},{"funder_name":"NCI NIH HHS","grant_id":"75N91019D00024","title":null},{"funder_name":"Intramural NIH HHS","grant_id":"ZIA BC011953","title":null}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"green","license":"public-domain","oa_locations":[{"url":"https://doi.org/10.1101/2024.09.27.615429","host_type":"repository"},{"url":"https://doi.org/10.1101/2024.09.27.615429","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2024.09.27.615429","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/39386738","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11463583","host_type":"repository"},{"url":"http://dx.doi.org/10.1101/2024.09.27.615429","host_type":""}],"fields_of_study":["Viral-associated cancers and disorders","Histiocytic Disorders and Treatments","CNS Lymphoma Diagnosis and Treatment","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["Sarcoma","Kaposi's sarcoma-associated herpesvirus","Biology","Computational biology","Human herpesvirus","Human immunodeficiency virus (HIV)","Virology","Cancer research","Medicine","Herpesviridae","Pathology","Viral disease","Article"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T10:56:09.811499Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}