title: Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells.
abstract: Special AT-rich sequence-binding protein 1 (Satb1) governs genome-wide transcriptional programs. Using a conditional knockout mouse, we find that Satb1 is required for normal differentiation of conventional dendritic cells (DCs). Furthermore, Satb1 governs the differentiation of inflammatory DCs by regulating major histocompatibility complex class II (MHC II) expression through Notch1 signaling. Mechanistically, Satb1 binds to the Notch1 promoter, activating Notch expression and driving RBPJ occupancy of the H2-Ab1 promoter, which activates MHC II transcription. However, tumor-driven, unremitting expression of Satb1 in activated Zbtb46(+) inflammatory DCs that infiltrate ovarian tumors results in an immunosuppressive phenotype characterized by increased secretion of tumor-promoting Galectin-1 and IL-6. In vivo silencing of Satb1 in tumor-associated DCs reverses their tumorigenic activity and boosts protective immunity. Therefore, dynamic fluctuations in Satb1 expression govern the generation and immunostimulatory activity of steady-state and inflammatory DCs, but continuous Satb1 overexpression in differentiated DCs converts them into tolerogenic/pro-inflammatory cells that contribute to malignant progression.
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Amelia J
authors.initials: AJ
authors.lastname: Tesone
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Rutkowski
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Brencicova
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Svoronos
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Perales-Puchalt
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Stephen
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Allegrezza
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Kyle K
authors.initials: KK
authors.lastname: Payne
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Nguyen
authors.affiliation: Center for Systems and Computational Biology, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Jayamanna
authors.initials: J
authors.lastname: Wickramasinghe
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania, Philadelphia, PA 19104-1693, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Tchou
authors.affiliation: Helen F. Graham Cancer Center, Christiana Care Health System, 4701 Ogletown-Stanton Road, Newark, DE 19713, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Borowsky
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME-CONICET), C1428ADN Buenos Aires, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Center for Systems and Computational Biology, the Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Kossenkov
authors.affiliation: Tumor Microenvironment and Metastasis Program, the Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: jrconejo@wistar.org.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Conejo-Garcia
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D037483:Galectin 1 / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D036961:Matrix Attachment Region Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology
chemical_list: D037483:Galectin 1; D000949:Histocompatibility Antigens Class II; D006657:Histones; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D015850:Interleukin-6; D036961:Matrix Attachment Region Binding Proteins; C497762:Notch1 protein, mouse; D034741:RNA, Small Interfering; C497571:Rbpj protein, mouse; D051881:Receptor, Notch1; C469541:Satb1 protein, mouse; D014157:Transcription Factors; C574226:Zbtb46 protein, mouse; C081018:histone H2B type 1-A; C577686:interleukin-6, mouse