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

Project: Research project

Project Details

Description

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.
StatusActive
Effective start/end date8/1/217/31/23

Funding

  • National Cancer Institute (1R21CA265574-01)

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