# Mechanisms of KSHV-induced endothelial cell loss of contact inhibition of proliferation

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $494,501

## Abstract

SUMMARY
Kaposi’s Sarcoma-associated herpesvirus (KSHV) causes the AIDS-defining cancer Kaposi’s Sarcoma (KS).
The KSHV-infected KS tumor cells (KSCs) express proliferation markers, indicating a loss of contact inhibition
of proliferation (CIP). CIP is considered a tumor suppressive pathway, and loss of CIP is a crucial feature of
oncogenic transformation in solid tumors. How KSHV antagonizes CIP is not known. The KS tumor cells most
likely originate from microvascular lymphatic endothelial cells (LECs). While LECs therefore represent a
relevant model for studies of KS, KSHV-induced proliferation after de novo infection of primary human LECs
has not been demonstrated. We have developed a protocol for KSHV infection of primary human LECs that
allows us to measure KSHV-induced loss of CIP. The central hypothesis underlying this application is that
KSHV-induced loss of CIP is a critical driving feature of oncogenesis in KS. Our preliminary work shows that
the KSHV miR-K10 miRNAs contribute substantially to the KSHV-induced loss of CIP in LECs but are not the
only viral determinants of this phenotype. Our results furthermore implicate viral repression of p27, disruption
of adherens junctions (AJs), and deregulation of the cytoskeleton and vesicular trafficking in KSHV-mediated
loss of CIP. To test our hypothesis and elucidate the mechanisms underlying KSHV-induced loss of CIP, we
propose three Specific Aims. In Specific Aim 1, we will determine the expression of the four miR-K10 miRNAs
in KSHV-infected LECs and KS. We will also define their individual contributions to the KSHV-induced loss of
CIP. In Specific Aim 2, we will identify the mechanisms underlying the miR-K10-induced loss of CIP in KSHV-
infected LECs. In Specific Aim 3, we will identify other viral genes that promote the KSHV-induced loss of CIP.
The proposed study is innovative because our model provides rigorously defined experimental settings that
enable the analysis of KSHV-induced loss of CIP after infection of a primary human cell type with relevance to
KS. This work is significant because it will establish the viral determinants of KSHV-induced LEC proliferation,
thereby explaining oncogenic mechanisms in KS. Results will be impactful since CIP is a tumor-suppressive
mechanism. Understanding how KSHV overcomes CIP will help us to explain how KSHV causes KS and could
potentially be exploited for therapeutic intervention in KS.

## Key facts

- **NIH application ID:** 10762813
- **Project number:** 1R01CA285193-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Eva Henriette Gottwein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $494,501
- **Award type:** 1
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10762813

## Citation

> US National Institutes of Health, RePORTER application 10762813, Mechanisms of KSHV-induced endothelial cell loss of contact inhibition of proliferation (1R01CA285193-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10762813. Licensed CC0.

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