title: A core of kinase-regulated interactomes defines the neoplastic MDSC lineage.
abstract: Myeloid-derived suppressor cells (MDSCs) differentiate from bone marrow precursors, expand in cancer-bearing hosts and accelerate tumor progression. MDSCs have become attractive therapeutic targets, as their elimination strongly enhances anti-neoplastic treatments. Here, immature myeloid dendritic cells (DCs), MDSCs modeling tumor-infiltrating subsets or modeling non-cancerous (NC)-MDSCs were compared by in-depth quantitative proteomics. We found that neoplastic MDSCs differentially expressed a core of kinases which controlled lineage-specific (PI3K-AKT and SRC kinases) and cancer-induced (ERK and PKC kinases) protein interaction networks (interactomes). These kinases contributed to some extent to myeloid differentiation. However, only AKT and ERK specifically drove MDSC differentiation from myeloid precursors. Interfering with AKT and ERK with selective small molecule inhibitors or shRNAs selectively hampered MDSC differentiation and viability. Thus, we provide compelling evidence that MDSCs constitute a distinct myeloid lineage distinguished by a "kinase signature" and well-defined interactomes. Our results define new opportunities for the development of anti-cancer treatments targeting these tumor-promoting immune cells.
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.|Immunomodulation Group, Division of Infection and Immunity, University College, London, UK.
authors: Maria
authors: M
authors: Gato-Cañas
authors: Proteomics Unit, Navarrabiomed-FMS, Proteored-ISCIII IdiSNA, Pamplona, Spain.
authors: Xabier
authors: X
authors: Martinez de Morentin
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.|Immunomodulation Group, Division of Infection and Immunity, University College, London, UK.
authors: Idoia
authors: I
authors: Blanco-Luquin
authors: Proteomics Unit, Navarrabiomed-FMS, Proteored-ISCIII IdiSNA, Pamplona, Spain.
authors: Joaquin
authors: J
authors: Fernandez-Irigoyen
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.
authors: Isabel
authors: I
authors: Zudaire
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.|Immunomodulation Group, Division of Infection and Immunity, University College, London, UK.
authors: Therese
authors: T
authors: Liechtenstein
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.|Hospital de Navarra, Department of Oncology, IdiSNA, Pamplona, Spain.
authors: Hugo
authors: H
authors: Arasanz
authors: Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, IdiSNA, Pamplona, Spain.
authors: Teresa
authors: T
authors: Lozano
authors: Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, IdiSNA, Pamplona, Spain.
authors: Noelia
authors: N
authors: Casares
authors: Structural Genomics Consortium (SGC), University of Oxford, Headington, UK.
authors: Apirat
authors: A
authors: Chaikuad
authors: Structural Genomics Consortium (SGC), University of Oxford, Headington, UK.|Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt, Germany.
authors: Stefan
authors: S
authors: Knapp
authors: Cancer Epigenetics Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.
authors: David
authors: D
authors: Guerrero-Setas
authors: Immunomodulation Group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.|Immunomodulation Group, Division of Infection and Immunity, University College, London, UK.
authors: David
authors: D
authors: Escors
authors: Protein Production Unit, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain.
authors: Grazyna
authors: G
authors: Kochan
authors: Proteomics Unit, Navarrabiomed-FMS, Proteored-ISCIII IdiSNA, Pamplona, Spain.
authors: Enrique
authors: E
authors: Santamaría
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D003713:Dendritic Cells / Q000166:cytology; D017097:Electric Impedance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology* / Q000276:immunology; D009369:Neoplasms / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D034741:RNA, Small Interfering; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex
keywords: MDSC; interactomes; kinases; proteomics; therapeutic targets