1. Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells
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Eva Brencicova, Amelia J. Tesone, Alfredo Perales-Puchalt, Mark E. Borowsky, Jose R. Conejo-Garcia, Jayamanna Wickramasinghe, Andrew V. Kossenkov, Julia Tchou, Gabriel A. Rabinovich, Jenny M. Nguyen, Nikolaos Svoronos, Michael J. Allegrezza, Tom L. Stephen, Kyle K. Payne, and Melanie R. Rutkowski
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0301 basic medicine ,Galectin 1 ,Cellular differentiation ,Immune tolerance ,Histones ,purl.org/becyt/ford/1 [https] ,Mice ,0302 clinical medicine ,Conditional gene knockout ,TRANSCRIPTION FACTOR ,RNA, Small Interfering ,Receptor, Notch1 ,Promoter Regions, Genetic ,Mice, Knockout ,Ovarian Neoplasms ,Cell Differentiation ,SATB1 ,Bioquímica y Biología Molecular ,3. Good health ,Cell biology ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,030220 oncology & carcinogenesis ,Galectin-1 ,Female ,Signal transduction ,CIENCIAS NATURALES Y EXACTAS ,Protein Binding ,Signal Transduction ,Biology ,DENDRITIC CELLS ,Article ,General Biochemistry, Genetics and Molecular Biology ,Ciencias Biológicas ,03 medical and health sciences ,INFLAMMATION ,Immune Tolerance ,Animals ,Humans ,IMMUNE TOLERANCE ,purl.org/becyt/ford/1.6 [https] ,Transcription factor ,Cell Proliferation ,Interleukin-6 ,RBPJ ,Histocompatibility Antigens Class II ,Dendritic Cells ,Matrix Attachment Region Binding Proteins ,030104 developmental biology ,Immunology ,Neoplasm Transplantation ,Transcription Factors - 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. Fil: Tesone, Amelia J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Rutkowski, Melanie R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Brencicova, Eva. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Svoronos, Nikolaos. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Perales Puchal, Alfredo. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Stephen, Tom L.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Allegrezza, Michael J.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Payne, Kyle K.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Nguyen, Jenny M.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos Fil: Wickramasinghe, Jayamanna. The Wistar Institute. Center for Systems and Computational Biology; Estados Unidos Fil: Tchou, Julia. University of Pennsylvania; Estados Unidos Fil: Borowsky, Mark E.. Christiana Care Health System. Helen F. Graham Cancer Center; Estados Unidos Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Kossenkov, Andrew V.. The Wistar Institute. Center for Systems and Computational Biology; Estados Unidos Fil: Conejo Garcia, José R.. The Wistar Institute. Tumor Microenvironment and Metastasis Program; Estados Unidos
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