Research Article: KSHV-induced ligand mediated activation of PDGF receptor-alpha drives Kaposi’s sarcomagenesis

Date Published: July 9, 2018

Publisher: Public Library of Science

Author(s): Lucas E. Cavallin, Qi Ma, Julian Naipauer, Sachin Gupta, Mani Kurian, Paola Locatelli, Paolo Romanelli, Mehrdad Nadji, Pascal J. Goldschmidt-Clermont, Enrique A. Mesri, Blossom Damania.

http://doi.org/10.1371/journal.ppat.1007175

Abstract

Kaposi’s sarcoma (KS) herpesvirus (KSHV) causes KS, an angiogenic AIDS-associated spindle-cell neoplasm, by activating host oncogenic signaling cascades through autocrine and paracrine mechanisms. Tyrosine kinase receptor (RTK) proteomic arrays, identified PDGF receptor-alpha (PDGFRA) as the predominantly-activated RTK in KSHV-induced mouse KS-tumors. We show that: 1) KSHV lytic replication and the vGPCR can activate PDGFRA through upregulation of its ligands PDGFA/B, which increase c-myc, VEGF and KSHV gene expression in infected cells 2) KSHV infected spindle cells of most AIDS-KS lesions display robust phospho-PDGFRA staining 3) blocking PDGFRA-signaling with N-acetyl-cysteine, RTK-inhibitors Imatinib and Sunitinib, or dominant-negative PDGFRA inhibits tumorigenesis 4) PDGFRA D842V activating-mutation confers resistance to Imatinib in mouse-KS tumorigenesis. Our data show that KSHV usurps sarcomagenic PDGFRA signaling to drive KS. This and the fact that PDGFRA drives non-viral sarcomas highlights the importance for KSHV-induced ligand-mediated activation of PDGFRA in KS sarcomagenesis and shows that this oncogenic axis could be successfully blocked to impede KS tumor growth.

Partial Text

Kaposi’s sarcoma herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS) [1–4]. KS is a major cancer associated with AIDS (AIDS-KS) and is the most prevalent type of cancer affecting men and children in Africa [2, 3, 5]. It is characterized by spindle cell proliferation, intense angiogenesis and erythrocyte extravasation with variable inflammatory infiltrates [2, 3]. Although the incidence of AIDS-KS in the western world has markedly declined since the wide-spread implementation of HAART, a significant percentage of AIDS-KS patients never achieve total remission [5–7]. Moreover, KSHV prevalence and KS incidence appear to be increasing, even in HAART treated HIV patients with controlled viremias [8, 9]. Understanding the interplay of viral and host factors in KS oncogenesis is critical for the rational development of new therapies [10, 11]. Many host signaling cascades co-opted by KSHV including PI3K/AKT/mTORC, NFkB and Notch are critical for cell-specific mechanisms of transformation and their identification is paving the way to therapeutic target discovery [4, 12–15].

Using kinase proteomic arrays to rank host-signaling pathways activated in a mouse model of KSHV tumorigenesis, we found that activated PDGF receptor-alpha (PDGFRA) is a predominant oncogenic RTK in KS. We showed that KSHV can activate sarcomagenic PDGFRA signaling through upregulation of PDGFs by KSHV lytic genes including vGPCR, we show that blocking PDGFRA signaling is anti-tumorigenic and we show that PDGFRA is prominently phosphorylated in KS (Fig 10).

 

Source:

http://doi.org/10.1371/journal.ppat.1007175