title: Loss of Host Type-I IFN Signaling Accelerates Metastasis and Impairs NK-cell Antitumor Function in Multiple Models of Breast Cancer.
abstract: Metastatic progression is the major cause of breast cancer-related mortality. By examining multiple syngeneic preclinical breast cancer models in mice lacking a functional type-I interferon receptor (Ifnar1(-/-) mice), we show that host-derived type-I interferon (IFN) signaling is a critical determinant of metastatic spread that is independent of primary tumor growth. In particular, we show that bone metastasis can be accelerated in Balb/c Ifnar1(-/-) mice bearing either 4T1 or 66cl4 orthotopic tumors and, for the first time, present data showing the development of bone metastasis in the C57Bl/6 spontaneous MMTV-PyMT-driven model of tumorigenesis. Further exploration of these results revealed that endogenous type-I IFN signaling to the host hematopoietic system is a key determinant of metastasis-free survival and critical to the responsiveness of the circulating natural killer (NK)-cell population. We find that in vivo-stimulated NK cells derived from wild-type, but not Ifnar1(-/-), mice can eliminate the 4T1 and 66cl4 breast tumor lines with varying kinetics in vitro. Together, this study indicates that the dysregulated immunity resulting from a loss of host type-I IFN signaling is sufficient to drive metastasis, and provides a rationale for targeting the endogenous type-I IFN pathway as an antimetastatic strategy.
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Jai
authors.initials: J
authors.lastname: Rautela
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Nikola
authors.initials: N
authors.lastname: Baschuk
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Clare Y
authors.initials: CY
authors.lastname: Slaney
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Krishnath M
authors.initials: KM
authors.lastname: Jayatilleke
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Kun
authors.initials: K
authors.lastname: Xiao
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Bidwell
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Erin C
authors.initials: EC
authors.lastname: Lucas
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
authors.forename: Edwin D
authors.initials: ED
authors.lastname: Hawkins
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Lock
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia. Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Clayton, Victoria, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.affiliation: Department of Immunology, Monash University Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Möller
authors.affiliation: Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia. Belinda.Parker@latrobe.edu.au.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Parker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001859:Bone Neoplasms / Q000276:immunology / Q000556:secondary*; D018450:Disease Progression; D005260:Female; D007370:Interferon Type I / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency; D015398:Signal Transduction / Q000276:immunology
chemical_list: D007370:Interferon Type I; D017471:Receptors, Interferon