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A core of kinase-regulated interactomes defines the neoplastic MDSC lineage

2015; Impact Journals LLC; Volume: 6; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.4746

1949-2553

María Gato, Xabier Martínez de Morentin, Idoia Blanco‐Luquin, Joaquín Fernández‐Irigoyen, Isabel Zudaire, Thérèse Liechtenstein, Hugo Arasanz, Teresa Lozano, Noëlia Casares, A. Chaikuad, Stefan Knapp, David Guerrero‐Setas, David Escors, Grazyna Kochan, Enrique Santamaría,

Sphingolipid Metabolism and Signaling

// Maria Gato-Cañas 1, 2, * , Xabier Martinez de Morentin 3, * , Idoia Blanco-Luquin 1, 2, * , Joaquin Fernandez-Irigoyen 3, * , Isabel Zudaire 1 , Therese Liechtenstein 1, 2 , Hugo Arasanz 1, 4 , Teresa Lozano 5 , Noelia Casares 5 , Apirat Chaikuad 6 , Stefan Knapp 6, 7 , David Guerrero-Setas 8 , David Escors 1, 2 , Grazyna Kochan 9 , Enrique Santamaría 3 1 Immunomodulation group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain 2 Immunomodulation group, Division of Infection and Immunity, University College London, UK 3 Proteomics Unit, Navarrabiomed-FMS, Proteored-ISCIII IdiSNA, Pamplona, Spain 4 Hospital de Navarra, Department of Oncology, IdiSNA, Pamplona, Spain 5 Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, IdiSNA, Pamplona, Spain 6 Structural Genomics Consortium (SGC), University of Oxford, Headington, UK 7 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt, Germany 8 Cancer Epigenetics group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain 9 Protein Production Unit, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain * These authors have contributed equally to this work Correspondence to: David Escors, e-mail: descorsm@navarra.es Grazyna Kochan, e-mail: grazyna.kochan@navarra.es Enrique Santamaría, e-mail: esantamma@navarra.es Keywords: MDSC, proteomics, interactomes, kinases, therapeutic targets Received: May 25, 2015 Accepted: July 13, 2015 Published: July 23, 2015 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.