Flipping the script: An oncogenic herpesvirus trapped in its cancer

Kaposi sarcoma herpesvirus (KSHV) drives multiple cancers including Kaposi sarcoma (KS). Pre-clinical animal models are needed to define virus-host interactions driving oncogenesis and to test novel therapies. We previously showed that KS skin implants in immunodeficient mice maintain KSHV-infected endothelial cells but remain confined to the implant borders. Here, we report that heterotypic implantation of KS from a patient with an anaplastic variant into a mouse kidney led to rapid tumor expansion that maintained LANA expression through six serial passages. This patient-derived xenograft (KS-PDX) recapitulates the atypical pathology of neoplastic non-spindled endothelial cells with a high mitotic index, matching the input biopsy. My collaborators discovered that key tumor suppressors and regulatory proteins are mutated in anaplastic KS, and spatial profiling revealed a dramatic transcriptional shift. Angiogenic and inflammatory pathways characteristic of conventional KS are downregulated, while pathways consistent with uncontrolled cell growth driven by host mutations are upregulated in anaplastic KS. Genomic instability extends to KSHV itself; sequencing reveals an unprecedented loss of two-thirds of the viral genome, leaving a truncated genome in the PDX identical to that found in patient tumor tissue with anaplastic pathology. Retained viral genes encompass the latency locus with known oncogenic properties, confirmed as expressed by RNAseq, while many genes essential to lytic replication and virion production are lost. In conclusion, my laboratory, working in collaboration with clinicians, computational scientists, and pathologists, has identified an aggressive anaplastic KS variant that is propogated as a PDX and recapitulates molecular and histopathological features of the patient's disease. This anaplastic KS-PDX model offers a unique opportunity to study the function of the retained viral genes expressed from a viral genome so destabilized that it is effectively locked in a self-perpetuating oncogenic state.