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First ever genetic pathway mapped for MDSC cancer progression.

An international collaboration led by Johns Hopkins University successfully established a visual mapping of the molecular pathway of myeloid derived suppressor cell (MDSC) cancer by way of an interactome. The damage and immune suppression the cells cause are not fully understood, however this is a major stepping stone in creating necessary transparency. The illustrative map will allow scientists to understand MDSC conditions, and create the means to infiltrate them.  The opensource study is published in the journal Oncotarget.

Myeloid derived suppressor cells (MDSC) are a heterogenous population of immune cells from the myeloid lineage, originating from bone marrow stem cells which are progenitors of granulocytes, macrophages and dendritic cells. These cells possess strong immunosuppressive activities.  MDSC suppresses the activity of various types of immune cells and contributes to tumour progression by promoting tumor angiogenesis and metastasis. Clinical and experimental evidence has shown that cancer tissues with high infiltration of MDSC are associated with poor patient prognosis and resistance to therapies thus making them an extremely important therapeutic target.

MDSC utilize multiple signalling cascades to expand their population. However, understanding the epigenetic networks where fine-tuning of these mechanisms occurs is lacking. The team aimed to compile a comprehensive picture of MDSC molecular networks in mouse models of colon and breast cancers by generating an MDSC interactome map using gene sequencing and various bioinformatic programmes. This new method has, in effect, produced a new way to map the interactions or interconnections between genes formed by transcription factors and resulting in the formation of cancer.

To test these bioinformatics and sequencing results the team returned to previous studies by the University of Padua where the C/EBPbeta transcription factor was proven to regulate both splenic and peritumoral MDSC. These previous results were replicated correctly.  In addition to these results the current study also identified EGR1, c-jun, HIF1A and c-myc in the regulation of MDSC in tumour infiltrates after sequencing over 5,000 genes.

The team also identified infiltrating MDSC as additionally utilising other EMT-related factors, namely TWIST and SNAIL (SNAI1) activated by the c-myc and HIF1A transcription factors.  These loci and epigenetic changes have not been seen in previous studies.  The interactome analysis of transcription factors therefore suggest their cell type- and disease type-specific contribute to a MDSC phenotype.

In conclusion, a quick and concise interactome analysis where the interaction and promiscuity of genes with each other are mapped is a powerful tool in defining the role MDSC in the formation of different types of cancers.  The team now how hope to investigate inhibitive compounds for these newly found targets.

Source:  Insilico Medicine, Inc

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.  Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer.  Zhavoronkov et al 2014.
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. Interactome analysis of myeloid-derived suppressor cells in murine models of colon and breast cancer. Zhavoronkov et al 2014.

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