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. 2014 Nov 30;5(22):11345-53.
doi: 10.18632/oncotarget.2489.

Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer

Alexander M Aliper  1 , Victoria P Frieden-Korovkina  2 , Anton Buzdin  3 , Sergey A Roumiantsev  4 , Alex Zhavoronkov  5
Affiliations

Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer

Alexander M Aliper et al. Oncotarget. .

Abstract

In solid cancers, myeloid derived suppressor cells (MDSC) infiltrate (peri)tumoral tissues to induce immune tolerance and hence to establish a microenvironment permissive to tumor growth. Importantly, the mechanisms that facilitate such infiltration or a subsequent immune suppression are not fully understood. Hence, in this study, we aimed to delineate disparate molecular pathways which MDSC utilize in murine models of colon or breast cancer. Using pathways enrichment analysis, we completed interactome maps of multiple signaling pathways in CD11b+/Gr1(high/low) MDSC from spleens and tumor infiltrates of mice with c26GM colon cancer and tumor infiltrates of MDSC in 4T1 breast cancer. In both cancer models, infiltrating MDSC, but not CD11b+ splenic cells, have been found to be enriched in multiple signaling molecules suggestive of their enhanced proliferative and invasive phenotypes. The interactome data has been subsequently used to reconstruct a previously unexplored regulation of MDSC cell cycle by the c-myc transcription factor which was predicted by the analysis. Thus, this study represents a first interactome mapping of distinct multiple molecular pathways whereby MDSC sustain cancer progression.

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Figures

Figure 1
Figure 1. Comparative analysis of MDSC transcription factors
(A) Splenic CD11b+ MDSC from c26GM colon cancer; (B) infiltrating CD11b+ MDSC from c26GM colon cancer; and (C) infiltrating CD11b+ MDSC from 4T1 breast cancer have been analyzed for an enrichment in transcription factors vs. healthy CD11b+ splenocytes using a pathway analysis tool MetaCore™. Higher z-scores (X axis) denote enhanced contributions (p<0.05, N=3 in each group).
Figure 2
Figure 2. Comparative analysis of MDSC kinases
(A) Splenic CD11b+ MDSC from c26GM colon cancer; (B) infiltrating CD11b+ MDSC from c26GM colon cancer; and (C) infiltrating CD11b+ MDSC from 4T1 breast cancer have been analyzed for an enrichment in kinases using a pathway analysis tool MetaCore™. Higher z-scores (X axis) denote enhanced contributions (p<0.05, N=3 in each group).
Figure 3
Figure 3. Comparative analysis of MDSC proteases
(A) Splenic CD11b+ MDSC from c26GM colon cancer; (B) infiltrating CD11b+ MDSC from c26GM colon cancer; and (C) infiltrating CD11b+ MDSC from 4T1 breast cancer have been analyzed for an enrichment in proteases using a pathway analysis tool MetaCore™. Higher z-scores (X axis) denote enhanced contributions (p<0.05, N=3 in each group).
Figure 4
Figure 4. Reconstruction of putative c-myc-dependent signaling pathways in MDSC
Circled numbers represent experimental groups 1, 2 and 3 respectively. The red bars above group numbers indicate an up-regulation whereas the blue bars represent down-regulation. The green, red and gray arrows denote activating, inhibitory and causative/unspecified interactions, respectively.
See this image and copyright information in PMC

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