title: The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells.
abstract: Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human data set analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases.
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Cuijuan
authors.initials: C
authors.lastname: Yu
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Gao
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Welte
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Muscarella
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Tian
authors.affiliation: NCI Center for Modeling Cancer Development, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.affiliation: NCI Center for Modeling Cancer Development, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Radiology, Southeast University School of Medicine, Nanjing 210018, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Shiyu
authors.initials: S
authors.lastname: Du
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Tao
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Brendan
authors.initials: B
authors.lastname: Lee
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Westbrook
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; NCI Center for Modeling Cancer Development, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Systems Medicine and Bioengineering, The Methodist Hospital Research Institute, Weill Cornell Medical College, 6670 Bertner Avenue, Houston, TX 77030, USA; Department of Radiology, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77459, USA.
authors.forename: Stephen T C
authors.initials: ST
authors.lastname: Wong
authors.affiliation: Cancer Program, the Eli and Edythe L. Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Rosen
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: C Kent
authors.initials: CK
authors.lastname: Osborne
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: xiangz@bcm.edu.
authors.forename: Xiang H-F
authors.initials: XH
authors.lastname: Zhang
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009367:Neoplasm Staging; D010012:Osteogenesis / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D015820:Cadherins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases