title: Disruption of follicular dendritic cells-follicular lymphoma cross-talk by the pan-PI3K inhibitor BKM120 (Buparlisib).
abstract: OBJECTIVE
  To uncover the signaling pathways underlying follicular lymphoma-follicular dendritic cells (FL-FDC) cross-talk and its validation as new targets for therapy.
  
  
  METHODS
  FL primary cells and cell lines were cocultured in the presence or absence of FDC. After 24 and 48 hours, RNA was isolated from FL cells and subjected to gene expression profiling (GEP) and data meta-analysis using DAVID and GSEA softwares. Blockade of PI3K pathway by the pan-PI3K inhibitor BKM120 (buparlisib; Novartis Pharmaceutical Corporation) and the effect of PI3K inhibition on FL-FDC cross-talk were analyzed by means of ELISA, RT-PCR, human umbilical vein endothelial cell tube formation, adhesion and migration assays, Western blot, and in vivo studies in mouse FL xenografts.
  
  
  RESULTS
  GEP of FL-FDC cocultures yields a marked modulation of FL transcriptome by FDC. Pathway assignment by DAVID and GSEA software uncovered an overrepresentation of genes related to angiogenesis, cell adhesion, migration, and serum-response factors. We demonstrate that the addition of the pan-PI3K inhibitor BKM120 to the cocultures was able to downregulate the expression and secretion of proangiogenic factors derived from FL-FDC cocultures, reducing in vitro and in vivo angiogenesis. Moreover, BKM120 efficiently counteracts FDC-mediated cell adhesion and impedes signaling and migration induced by the chemokine CXCL12. BKM120 inhibits both constitutive PI3K/AKT pathway and FDC- or CXCL12-induced PI3K/AKT pathway, hampers FDC survival signaling, and reduces cell proliferation of FL cells in vitro and in mouse xenografts.
  
  
  CONCLUSIONS
  These data support the use of BKM120 in FL therapy to counteract microenvironment-related survival signaling in FL cells.
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Alba
authors.initials: A
authors.lastname: Matas-Céspedes
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Vanina
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Bioinformatics Core Facility;
authors.forename: Susana G
authors.initials: SG
authors.lastname: Kalko
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Anna
authors.initials: A
authors.lastname: Vidal-Crespo
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.affiliation: Bioinformatics Core Facility;
authors.forename: Teresa
authors.initials: T
authors.lastname: Casserras
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Patricia
authors.initials: P
authors.lastname: Balsas
authors.affiliation: Hematopathology Unit, Department of Pathology; and.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Giné
authors.affiliation: Hematopathology Unit, Department of Pathology; and.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology;
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.affiliation: Department of Hematology, Hospital Clínic, IDIBAPS, Barcelona, Spain.
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology; Hematopathology Unit, Department of Pathology; and.
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
authors.affiliation: Authors' Affiliations: Experimental Therapeutics in Lymphoid Malignancies Group, Department of Hemato-Oncology; pperez@clinic.ub.es.
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D054377:Chemokine CXCL12 / Q000378:metabolism; D016000:Cluster Analysis; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D054377:Chemokine CXCL12; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019718:Receptors, CXCR4