title: Endogenous dendritic cells from the tumor microenvironment support T-ALL growth via IGF1R activation.
abstract: Primary T-cell acute lymphoblastic leukemia (T-ALL) cells require stromal-derived signals to survive. Although many studies have identified cell-intrinsic alterations in signaling pathways that promote T-ALL growth, the identity of endogenous stromal cells and their associated signals in the tumor microenvironment that support T-ALL remains unknown. By examining the thymic tumor microenvironments in multiple murine T-ALL models and primary patient samples, we discovered the emergence of prominent epithelial-free regions, enriched for proliferating tumor cells and dendritic cells (DCs). Systematic evaluation of the functional capacity of tumor-associated stromal cells revealed that myeloid cells, primarily DCs, are necessary and sufficient to support T-ALL survival ex vivo. DCs support T-ALL growth both in primary thymic tumors and at secondary tumor sites. To identify a molecular mechanism by which DCs support T-ALL growth, we first performed gene expression profiling, which revealed up-regulation of platelet-derived growth factor receptor beta (Pdgfrb) and insulin-like growth factor I receptor (Igf1r) on T-ALL cells, with concomitant expression of their ligands by tumor-associated DCs. Both Pdgfrb and Igf1r were activated in ex vivo T-ALL cells, and coculture with tumor-associated, but not normal thymic DCs, sustained IGF1R activation. Furthermore, IGF1R signaling was necessary for DC-mediated T-ALL survival. Collectively, these studies provide the first evidence that endogenous tumor-associated DCs supply signals driving T-ALL growth, and implicate tumor-associated DCs and their mitogenic signals as auspicious therapeutic targets.
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Todd A
authors: TA
authors: Triplett
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Kim T
authors: KT
authors: Cardenas
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Jessica N
authors: JN
authors: Lancaster
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Zicheng
authors: Z
authors: Hu
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Hilary J
authors: HJ
authors: Selden
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Guadalupe J
authors: GJ
authors: Jasso
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Sadhana
authors: S
authors: Balasubramanyam
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712;
authors: Kathy
authors: K
authors: Chan
authors: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors: LiQi
authors: L
authors: Li
authors: Division of Biostatistics, Department of Health Sciences, University of Miami Miller School of Medicine, Miami, FL 33136; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136;
authors: Xi
authors: X
authors: Chen
authors: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030;
authors: Andrea N
authors: AN
authors: Marcogliese
authors: Division of Hematology/Oncology, Tennessee Valley Healthcare System and Vanderbilt University Medical Center, Nashville, TN 37232.
authors: Utpal P
authors: UP
authors: Davé
authors: Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
authors: Paul E
authors: PE
authors: Love
authors: Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX 78712; lehrlich@austin.utexas.edu.
authors: Lauren I R
authors: LI
authors: Ehrlich
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000276:immunology; D017451:Receptors, Somatomedin / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*
chemical_list: C000597236:IGF1R protein, human; D009363:Neoplasm Proteins; D017451:Receptors, Somatomedin; C000605860:PDGFRB protein, human; D017526:Receptor, IGF Type 1; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: IGF1R; T-ALL; dendritic cell; leukemia; tumor microenvironment