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.

Myeloid-Derived Suppressor Cells

“…Mouse MDSC were also characterized by specific proteome (37–39) and transcriptome (40, 41) profiles.…”

The paradoxical role of tumor-infiltrating immune cells in lung cancer

“…There are several mechanisms by which MDSCs suppress antitumor responses. MDSCs restrain T cell functions in tumor tissues and draining lymph nodes by using two enzymes involved in L-arginine metabolism: arginase-1(ARG-1), which depletes the milieu of L-arginine, and induced nitric oxide synthase 2 (iNOS2), which generates nitric oxide (NO) (46,47).…”

Human Pancreatic Cancer Cells Undergo Profound Metabolic Reprogramming Towards Cellular Stemness as Adaptation to Inhibition of the Akt Pathway

“…Inhibitory concentration 50 (IC50) to metformin and tigecycline for AsPC-1 cells was calculated by RTCA using increasing concentrations as described (Gato-Canas et al, 2015). PANC02 cells were adapted to toxic concentrations of AKT inhibitor X (10-DEBC hydrochloride, SIGMA, CAS number 925681-41-0), by continuous growth with AKTi through a step-by-step increase in concentration until reaching toxic concentrations (50 µM) to non-adapted cells during the course of one month.…”