Journal
ONCOTARGET
Volume 8, Issue 13, Pages 21609-21625Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.15450
Keywords
metastasis; CD274; bone marrow; stromal niche; MDSC
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Funding
- ERC Advanced Investigator Grant [Pa-CSC 233460]
- European Community [256974, 602783]
- SU2C Lustgarten CRUK Pancreatic Cancer Dream Team Award
- Pancreatic Cancer UK [RIF2014_04]
- Human Frontiers Scientific Program (HFSP) [RGP0004/2013]
- La Caixa Predoctoral Fellowship Programme
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The stromal microenvironment controls response to injury and inflammation, and is also an important determinant of cancer cell behavior. However, our understanding of its modulation by miRNA (miR) and their respective targets is still sparse. Here, we identified the miR-25-93-106b cluster and two new target genes as critical drivers for metastasis and immune evasion of cancer cells. Using miR-25-93-106b knockout mice or antagomiRs, we demonstrated regulation of the production of the chemoattractant CXCL12 controlling bone marrow metastasis. Moreover, we identified the immune checkpoint PD-L1 (CD274) as a novel miR-93/106b target playing a central role in diminishing tumor immunity. Eventually, upregulation of miR-93 and miR-106b via miR-mimics or treatment with an epigenetic reader domain (BET) inhibitor resulted in diminished expression of CXCL12 and PD-L1. These data suggest a potential new therapeutic rationale for use of BET inhibitors for dual targeting of cancers with strong immunosuppressive and metastatic phenotypes.
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