Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis.

Ramya Ramaswami, Takanobu Tagawa, Guruswamy Mahesh, Anna Serquina, Vishal Koparde, Kathryn Lurain, Sarah Dremel, Xiaofan Li, Ameera Mungale, Alex Beran, Zoe Weaver Ohler, Laura Bassel, Andrew Warner, Ralph Mangusan, Anaida Widell, Laurie T. Krug, Thomas S. Uldrick, Robert Yarchoan, Joseph M. Ziegelbauer

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background Kaposi sarcoma (KS) is a multicentric tumor caused by Kaposi sarcoma herpesvirus (KSHV) that leads to morbidity and mortality among people with HIV worldwide. KS commonly involves the skin but can occur in the gastrointestinal tract (GI) in severe cases. Methods RNA sequencing was used to compare the cellular and KSHV gene expression signatures of skin and GI KS lesions in 44 paired samples from 19 participants with KS alone or with concurrent KSHV-associated diseases. Analyses of KSHV expression from KS lesions identifed transcriptionally active areas of the viral genome. Results The transcript of an essential viral lytic gene, ORF75, was detected in 91% of KS lesions. Analyses of host genes identifed 370 diferentially expressed genes (DEGs) unique to skin KS and 58 DEGs unique to GI KS lesions as compared to normal tissue. Interleukin (IL)-6 and IL-10 gene expression were higher in skin lesions as compared to normal skin but not in GI KS lesions. Twenty-six cellular genes were diferentially expressed in both skin and GI KS tissues: these included Fms-related tyrosine kinase 4 (FLT4), encoding an angiogenic receptor, and Stanniocalcin 1 (STC1), a secreted glycoprotein. FLT4 and STC1 were further investigated in functional studies using primary lymphatic endothelial cells (LECs). In these models, KSHV infection of LECs led to increased tubule formation that was impaired upon knock-down of STC1 or FLT4. Conclusions This study of transcriptional profling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm.
Original languageEnglish
Article number653
Number of pages17
JournalJournal of translational medicine
DOIs
Publication statusPublished - 22 Sept 2023
Externally publishedYes

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