# KSHV-induced oncogenic changes in a primary human lymphatic endothelial cell model of Kaposi's Sarcoma

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2022 · $187,000

## Abstract

SUMMARY
Kaposi's Sarcoma-associated herpesvirus (KSHV) causes the AIDS-defining cancer Kaposi's Sarcoma (KS).
How KSHV infection causes KS is poorly understood, largely due to a lack of a rigorously defined primary
human cell culture model that recapitulates the proliferative features of the KSHV-infected tumor cells in KS.
KS tumor cells most likely originate from microvascular lymphatic endothelial cells (LECs). LECs therefore
represent a physiologically relevant model for studies of KS. We have developed a protocol for KSHV infection
of primary human LECs that allows us to measure KSHV-induced loss of contact inhibition of proliferation (CIP)
in 2D culture. Loss of CIP is a key feature of oncogenic transformation. Our central hypothesis is therefore that
KSHV can trigger oncogenic transformation of primary LECs, in a process that recapitulates KSHV-mediated
oncogenesis in Kaposi's Sarcoma. Our first objective is to determine if KSHV-infected LECs (KLECs) are fully
transformed and form xenograft tumors in immunodeficient mice. We additionally hypothesize that unknown
KSHV-induced changes in cellular gene expression drive the loss of CIP in our model. However, in our
preliminary bulk gene expression studies too many candidates for such changes exist to directly proceed to
mechanistic studies. Our second objective is therefore to establish which cellular gene expression changes
drive loss of CIP in KLECs. To test our hypothesis and achieve our objectives, we propose two Specific Aims,
i.e. we will: (1) determine whether KLECs are fully transformed and can form xenograft tumors in
immunodeficient mice, and (2) define gene expression trajectories that drive KSHV-induced oncogenic
changes in KLECs. The proposed study is innovative, because our model provides a set of rigorously defined
experimental settings that enable the study of oncogenic changes after KSHV infection of a primary human cell
type with relevance to KS. This work is significant, because it will establish whether KSHV-infected LECs are
indeed fully transformed and identify mechanisms of viral transformation in KS. Finally, the results will be
impactful, because our primary human cell-based model and its characterization will enable important in vitro
and, potentially, in vivo studies of the mechanisms underlying KS as well as the design of improved strategies
for therapeutic intervention.

## Key facts

- **NIH application ID:** 10457488
- **Project number:** 5R21CA265574-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Eva Henriette Gottwein
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $187,000
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10457488

## Citation

> US National Institutes of Health, RePORTER application 10457488, KSHV-induced oncogenic changes in a primary human lymphatic endothelial cell model of Kaposi's Sarcoma (5R21CA265574-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10457488. Licensed CC0.

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