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

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...

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Autores principales: Ramaswami, Ramya, Tagawa, Takanobu, Mahesh, Guruswamy, Serquina, Anna, Koparde, Vishal, Lurain, Kathryn, Dremel, Sarah, Li, Xiaofan, Mungale, Ameera, Beran, Alex, Ohler, Zoe Weaver, Bassel, Laura, Warner, Andrew, Mangusan, Ralph, Widell, Anaida, Ekwede, Irene, Krug, Laurie T., Uldrick, Thomas S., Yarchoan, Robert, Ziegelbauer, Joseph M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517594/
https://www.ncbi.nlm.nih.gov/pubmed/37740179
http://dx.doi.org/10.1186/s12967-023-04517-5
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author Ramaswami, Ramya
Tagawa, Takanobu
Mahesh, Guruswamy
Serquina, Anna
Koparde, Vishal
Lurain, Kathryn
Dremel, Sarah
Li, Xiaofan
Mungale, Ameera
Beran, Alex
Ohler, Zoe Weaver
Bassel, Laura
Warner, Andrew
Mangusan, Ralph
Widell, Anaida
Ekwede, Irene
Krug, Laurie T.
Uldrick, Thomas S.
Yarchoan, Robert
Ziegelbauer, Joseph M.
author_facet Ramaswami, Ramya
Tagawa, Takanobu
Mahesh, Guruswamy
Serquina, Anna
Koparde, Vishal
Lurain, Kathryn
Dremel, Sarah
Li, Xiaofan
Mungale, Ameera
Beran, Alex
Ohler, Zoe Weaver
Bassel, Laura
Warner, Andrew
Mangusan, Ralph
Widell, Anaida
Ekwede, Irene
Krug, Laurie T.
Uldrick, Thomas S.
Yarchoan, Robert
Ziegelbauer, Joseph M.
author_sort Ramaswami, Ramya
collection PubMed
description 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 identified 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 identified 370 differentially 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 differentially 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 profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04517-5.
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spelling pubmed-105175942023-09-24 Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis Ramaswami, Ramya Tagawa, Takanobu Mahesh, Guruswamy Serquina, Anna Koparde, Vishal Lurain, Kathryn Dremel, Sarah Li, Xiaofan Mungale, Ameera Beran, Alex Ohler, Zoe Weaver Bassel, Laura Warner, Andrew Mangusan, Ralph Widell, Anaida Ekwede, Irene Krug, Laurie T. Uldrick, Thomas S. Yarchoan, Robert Ziegelbauer, Joseph M. J Transl Med Research 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 identified 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 identified 370 differentially 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 differentially 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 profiling of KS tissue provides novel insights into the characteristics and pathogenesis of this unique virus-driven neoplasm. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-023-04517-5. BioMed Central 2023-09-22 /pmc/articles/PMC10517594/ /pubmed/37740179 http://dx.doi.org/10.1186/s12967-023-04517-5 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Ramaswami, Ramya
Tagawa, Takanobu
Mahesh, Guruswamy
Serquina, Anna
Koparde, Vishal
Lurain, Kathryn
Dremel, Sarah
Li, Xiaofan
Mungale, Ameera
Beran, Alex
Ohler, Zoe Weaver
Bassel, Laura
Warner, Andrew
Mangusan, Ralph
Widell, Anaida
Ekwede, Irene
Krug, Laurie T.
Uldrick, Thomas S.
Yarchoan, Robert
Ziegelbauer, Joseph M.
Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title_full Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title_fullStr Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title_full_unstemmed Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title_short Transcriptional landscape of Kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
title_sort transcriptional landscape of kaposi sarcoma tumors identifies unique immunologic signatures and key determinants of angiogenesis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10517594/
https://www.ncbi.nlm.nih.gov/pubmed/37740179
http://dx.doi.org/10.1186/s12967-023-04517-5
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