KSHV-infected endothelial cells expand and up-regulate angiogenic pathways and CXCR4 in patient-derived Kaposi...

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 established KS patient-derived xenografts (PDXs) through orthotopic implantation of cutaneous KS biopsies into immunodeficient mice. KS tumors were maintained in 27 of 28 PDXs until the experimental end point. KSHV latency-associated nuclear antigen-positive (LANA⁺) endothelial cells exhibited higher Ki-67 staining and increased density compared with their respective input biopsies. Spatial analysis of the PDXs revealed increased expression of viral transcripts from latent and lytic gene classes and enrichment in pathways of angiogenesis and endothelium development, similar to KS tumor biopsies. C-X-C chemokine receptor type 4 (CXCR4), a receptor for the inflammatory C-X-C motif chemokine ligand 12 (CXCL12), was more highly expressed in infected tumor cells than uninfected cells, suggesting a direct response to virus infection. Cells with fibroblast characteristics derived from 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 with those of patients who had KS alone. Together, the reproducible expansion of KSHV-infected endothelial cells in PDXs from multiple donors and the similar recapitulation of molecular and pathologic features of KS support KS PDXs as a preclinical model for the discovery of pathogenic mechanisms and candidate therapeutics.