title: SOX11 promotes tumor angiogenesis through transcriptional regulation of PDGFA in mantle cell lymphoma.
abstract: 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.
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Jara
authors.initials: J
authors.lastname: Palomero
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Maria Carmela
authors.initials: MC
authors.lastname: Vegliante
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Marta Leonor
authors.initials: ML
authors.lastname: Rodríguez
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Eguileor
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Castellano
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and.
authors.forename: Ester
authors.initials: E
authors.lastname: Planas-Rigol
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Pedro
authors.initials: P
authors.lastname: Jares
authors.affiliation: Department of Anatomic Pathology, Pharmacology and Microbiology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ribera-Cortada
authors.affiliation: Vasculitis Research Unit, Department of Autoimmune Diseases, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
authors.affiliation: Hematopathology Unit, Pathology Department, and Department of Anatomic Pathology, Pharmacology and Microbiology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Hematopathology Unit, Pathology Department, and.
authors.forename: Virginia
authors.identifier: http://orcid.org/0000-0002-3016-2874
authors.initials: V
authors.lastname: Amador
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000737:chemistry; D042783:Endothelial Cells / Q000166:cytology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D040901:Proteomics; D055751:SOXC Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; C097473:SOX11 protein, human; D055751:SOXC Transcription Factors; C075278:platelet-derived growth factor A