The miR-25-93-106b cluster regulates tumor metastasis and immune evasion via modulation of CXCL12 and PD-L1

Michele Cioffi, Sara M. Trabulo, Mireia Vallespinos, Deepak Raj, Tony Bou Kheir, Meng Lay Lin, Julfa Begum, Ann Marie Baker, Ala Amgheib, Jaimy Saif, Manuel Perez, Joaquim Soriano, Manuel Desco, Maria Victoria Gomez-Gaviro, Lorena Cusso, Diego Megias, Alexandra Aicher*, Christopher Heeschen

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

52 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)21609-21625
Number of pages17
JournalOncotarget
Volume8
Issue number13
DOIs
Publication statusPublished - 17 Feb 2017

Keywords

  • Bone marrow
  • CD274
  • MDSC
  • Metastasis
  • Stromal niche

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