Oncotarget

Research Papers:

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

Maria Gato-Cañas _, Xabier Martinez de Morentin, Idoia Blanco-Luquin, Joaquin Fernandez-Irigoyen, Isabel Zudaire, Therese Liechtenstein, Hugo Arasanz, Teresa Lozano, Noelia Casares, Apirat Chaikuad, Stefan Knapp, David Guerrero-Setas, David Escors, Grazyna Kochan and Enrique Santamaría

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Oncotarget. 2015; 6:27160-27175. https://doi.org/10.18632/oncotarget.4746

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Abstract

Maria Gato-Cañas1,2,*, Xabier Martinez de Morentin3,*, Idoia Blanco-Luquin1,2,*, Joaquin Fernandez-Irigoyen3,*, Isabel Zudaire1, Therese Liechtenstein1,2, Hugo Arasanz1,4, Teresa Lozano5, Noelia Casares5, Apirat Chaikuad6, Stefan Knapp6,7, David Guerrero-Setas8, David Escors1,2, Grazyna Kochan9, Enrique Santamaría3

1Immunomodulation group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain

2Immunomodulation group, Division of Infection and Immunity, University College London, UK

3Proteomics Unit, Navarrabiomed-FMS, Proteored-ISCIII IdiSNA, Pamplona, Spain

4Hospital de Navarra, Department of Oncology, IdiSNA, Pamplona, Spain

5Immunology and Immunotherapy Program, Center for Applied Medical Research, University of Navarra, IdiSNA, Pamplona, Spain

6Structural Genomics Consortium (SGC), University of Oxford, Headington, UK

7Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Frankfurt, Germany

8Cancer Epigenetics group, Navarrabiomed-FMS, IdiSNA, Pamplona, Spain

9Protein 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.


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