title: CSF1-ETS2-induced microRNA in myeloid cells promote metastatic tumor growth.
abstract: Metastasis of solid tumors is associated with poor prognosis and bleak survival rates. Tumor-infiltrating myeloid cells (TIMs) are known to promote metastasis, but the mechanisms underlying their collaboration with tumor cells remain unknown. Here, we report an oncogenic role for microRNA (miR) in driving M2 reprogramming in TIMs, characterized by the acquisition of pro-tumor and pro-angiogenic properties. The expression of miR-21, miR-29a, miR-142-3p and miR-223 increased in myeloid cells during tumor progression in mouse models of breast cancer and melanoma metastasis. Further, we show that these miRs are regulated by the CSF1-ETS2 pathway in macrophages. A loss-of-function approach utilizing selective depletion of the miR-processing enzyme Dicer in mature myeloid cells blocks angiogenesis and metastatic tumor growth. Ectopic expression of miR-21 and miR-29a promotes angiogenesis and tumor cell proliferation through the downregulation of anti-angiogenic genes such as Col4a2, Spry1 and Timp3, whereas knockdown of the miRs impedes these processes. miR-21 and miR-29a are expressed in Csf1r+ myeloid cells associated with human metastatic breast cancer, and levels of these miRs in CD115+ non-classical monocytes correlates with metastatic tumor burden in patients. Taken together, our results suggest that miR-21 and miR-29a are essential for the pro-tumor functions of myeloid cells and the CSF1-ETS2 pathway upstream of the miRs serves as an attractive therapeutic target for the inhibition of M2 remodeling of macrophages during malignancy. In addition, miR-21 and miR-29a in circulating myeloid cells may potentially serve as biomarkers to measure therapeutic efficacy of targeted therapies for CSF1 signaling.
authors.affiliation: 1] Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH, USA [2] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Mathsyaraja
authors.affiliation: 1] Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH, USA [2] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Thies
authors.affiliation: 1] Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH, USA [2] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Taffany
authors.affiliation: Department of Chemical Engineering, The Ohio State University, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Deighan
authors.affiliation: The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Fernandez
authors.affiliation: 1] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Shapiro
authors.affiliation: 1] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Pathology, Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Otero
authors.affiliation: The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Timmers
authors.affiliation: 1] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, OH, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Lustberg
authors.affiliation: 1] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Chemical Engineering, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chalmers
authors.affiliation: 1] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University College of Medicine, Columbus, OH, USA [3] Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.affiliation: 1] Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH, USA [2] The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Ostrowski
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016173:Macrophage Colony-Stimulating Factor; D035683:MicroRNAs; D050787:Proto-Oncogene Protein c-ets-2; C494069:ETS2 protein, human; C555159:MIRN142 microRNA, human; C524940:MIRN21 microRNA, human; C525067:MIR223, human; C532045:MIRN29a microRNA, human