KSHV-infected endothelial cells expand in Kaposi sarcoma xenografts, upregulating angiogenesis and CXCR4.

Kaposi sarcoma (KS) is an aggressive vascular tumor characterized by aberrant angiogenesis, driven by Kaposi sarcoma herpesvirus (KSHV)-infected spindle cells. A significant challenge in KS research has been the rapid loss of KSHV infection when tumor cells are explanted into traditional cell culture, hindering the study of pathogenic mechanisms and the development of effective therapeutics. There is a critical need for robust, in vivo preclinical models that faithfully maintain KSHV infection and recapitulate the complex molecular and pathological features of human KS tumors.

Researchers established KS patient-derived xenografts (PDXs) by orthotopically implanting cutaneous KS biopsies into immunodeficient mice. The study successfully maintained KS tumors in 27 of 28 PDXs until the experimental endpoint. They compared KSHV latency-associated nuclear antigen-positive (LANA+) endothelial cells in PDXs with their respective input biopsies using Ki-67 staining for proliferation and spatial analysis. They also performed gene expression analysis to assess viral transcripts and pathway enrichment.

The PDX models demonstrated reproducible expansion of KSHV-infected endothelial cells, with LANA+ endothelial cells exhibiting higher Ki-67 staining and increased density compared to input biopsies. Spatial analysis of the PDXs revealed increased expression of viral transcripts from both latent and lytic gene classes. Critically, these PDXs showed significant enrichment in pathways related to angiogenesis and endothelium development, closely mirroring the characteristics observed in human KS tumor biopsies. The C-X-C chemokine receptor type 4 (CXCR4), a receptor for CXCL12, was more highly expressed in infected tumor cells than in uninfected cells, suggesting a direct viral influence. > Fibroblast-like cells derived from these PDXs were permissive for de novo KSHV infection, and one lineage produced CXCL12, which was also elevated in the sera of patients with KSHV-associated diseases compared to those with KS alone.