SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma

• Published in: Blood Vol. 124; no. 14; pp. 2235 - 2247
• Main Authors: Palomero, Jara, Vegliante, Maria Carmela, Rodríguez, Marta Leonor, Eguileor, Álvaro, Castellano, Giancarlo, Planas-Rigol, Ester, Jares, Pedro, Ribera-Cortada, Inmaculada, Cid, Maria C., Campo, Elias, Amador, Virginia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-10-2014
• Subjects: Animals; Cell Movement; Cell Proliferation; Culture Media, Conditioned - chemistry; Endothelial Cells - cytology; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Silencing; Human Umbilical Vein Endothelial Cells; Humans; Lymphoma, Mantle-Cell - metabolism; Mice; Mice, SCID; Neoplasm Transplantation; Neovascularization, Pathologic; Platelet-Derived Growth Factor - metabolism; Proteomics; Signal Transduction; SOXC Transcription Factors - metabolism; Transcriptional Activation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-04-569566

SOX11 is overexpressed in several solid tumors and in the vast majority of aggressive mantle cell lymphomas (MCLs). We have recently proven that SOX11 silencing reduces tumor growth in a MCL xenograft model, consistent with the indolent clinical course of the human SOX11-negative mantle cell lymphoma (MCL). However, the direct oncogenic mechanisms and downstream effector pathways implicated in SOX11-driven transformation remain poorly understood. Here, we observed that SOX11-positive xenograft and human primary MCL tumors overexpressed angiogenic gene signatures and had a higher microvascular density compared with their SOX11-negative counterparts. Conditioned media of SOX11-positive MCL cell lines induced in vitro endothelial cell proliferation, migration, tube formation, and activation of downstream angiogenic pathways. We identified PDGFA as a SOX11 direct target gene upregulated in MCL cells whose inhibition impaired SOX11-enhanced in vitro angiogenic effects on endothelial cells. In addition, platelet-derived growth factor A (PDGFA) was overexpressed in SOX11-positive but not in SOX11-negative MCL. In vivo, imatinib impaired tumor angiogenesis and lymphoma growth in SOX11-positive MCL xenograft tumors. Overall, our results demonstrate a prominent role for SOX11 as a driver of proangiogenic signals in MCL, and highlight the SOX11-PDGFA axis as a potential therapeutic target for the treatment of this aggressive disease.
•SOX11 mediates regulation of angiogenesis via the PDGFA signaling pathway in MCL.•SOX11-dependent increased angiogenesis contributes to a more aggressive MCL phenotype.