title: Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils.
abstract: Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in peripheral tissues but not in the primary tumor. Production of these cells results from activation of a myeloid differentiation program in bone marrow (BM) by a novel mechanism in which tumor-derived granulocyte-colony stimulating factor (G-CSF) directs expansion and differentiation of hematopoietic stem cells to skew hematopoiesis toward the myeloid lineage. Chronic skewing of myeloid production occurred in parallel to a decrease in erythropoiesis in BM in mice with progressive disease. Significantly, we reveal that prolonged G-CSF stimulation is both necessary and sufficient for the distinguishing characteristics of tumor-induced immunosuppressive neutrophils. These results demonstrate that prolonged G-CSF may be responsible for both the development and activity of immunosuppressive neutrophils in cancer.
authors.affiliation: Department of Anatomy and.
authors.forename: Amy-Jo
authors.initials: AJ
authors.lastname: Casbon
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, and Division of Hematology/Oncology, University of California, San Francisco, CA 94143.
authors.forename: Damien
authors.initials: D
authors.lastname: Reynaud
authors.affiliation: Department of Anatomy and.
authors.forename: Chanhyuk
authors.initials: C
authors.lastname: Park
authors.affiliation: Department of Anatomy and.
authors.forename: Emily
authors.initials: E
authors.lastname: Khuc
authors.affiliation: Department of Anatomy and.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Gan
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, and Division of Hematology/Oncology, University of California, San Francisco, CA 94143.
authors.forename: Koen
authors.initials: K
authors.lastname: Schepers
authors.affiliation: The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, and Division of Hematology/Oncology, University of California, San Francisco, CA 94143.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Passegué
authors.affiliation: Department of Anatomy and zena.werb@ucsf.edu.
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000503:physiopathology*; D001973:Bromodeoxyuridine; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D006410:Hematopoiesis / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009504:Neutrophils / Q000276:immunology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D001973:Bromodeoxyuridine
keywords: cancer; hematopoiesis; immunology; myeloid-derived suppressor cells; stem cell biology