Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models

Li, X.; Weaver Ohler, Z.; Day, A.; Bassel, L.; Grosskopf, A.; Afsari, B.; Tagawa, T.; Custer, W.; Mangusan, R.; Lurain, K.; Yarchoan, R.; Ziegelbauer, J.; Ramaswami, R.; Krug, L. T.

doi:10.1101/2024.09.27.615429

bioRxiv · 10.1101/2024.09.27.615429

Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models

Li, X.·Weaver Ohler, Z.·Day, A.·Bassel, L.·Grosskopf, A.·Afsari, B.·Tagawa, T.·Custer, W.·Mangusan, R.·Lurain, K.·Yarchoan, R.·Ziegelbauer, J.·Ramaswami, R.·Krug, L. T.

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Abstract

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 de novo 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. One Sentence SummaryTumor 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.

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Li, X., Weaver Ohler, Z., Day, A., Bassel, L., Grosskopf, A., Afsari, B., Tagawa, T., Custer, W., Mangusan, R., Lurain, K., Yarchoan, R., Ziegelbauer, J., Ramaswami, R., Krug, L. T.. 2024-09-28. Mapping herpesvirus-driven impacts on the cellular milieu and transcriptional profile of Kaposi sarcoma in patient-derived mouse models. https://doi.org/10.1101/2024.09.27.615429

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