The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells

Hai Wang; Cuijuan Yu; Xia Gao; Thomas Welte; Aaron M Muscarella; Lin Tian; Hong Zhao; Zhen Zhao; Shiyu Du; Jianning Tao; Brendan Lee; Thomas F Westbrook; Stephen T C Wong; Xin Jin; Jeffrey M Rosen; C Kent Osborne; Xiang H-F Zhang

doi:10.1016/j.ccell.2014.11.017

The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells

Cancer Cell. 2015 Feb 9;27(2):193-210. doi: 10.1016/j.ccell.2014.11.017. Epub 2015 Jan 15.

Authors

Hai Wang¹, Cuijuan Yu¹, Xia Gao¹, Thomas Welte¹, Aaron M Muscarella², Lin Tian³, Hong Zhao⁴, Zhen Zhao⁵, Shiyu Du⁶, Jianning Tao⁷, Brendan Lee⁷, Thomas F Westbrook⁸, Stephen T C Wong⁹, Xin Jin¹⁰, Jeffrey M Rosen¹¹, C Kent Osborne¹², Xiang H-F Zhang¹³

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.
⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
⁸ 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.
⁹ 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.
¹⁰ Cancer Program, the Eli and Edythe L. Broad Institute, 415 Main Street, Cambridge, MA 02142, USA.
¹¹ 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.
¹² 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.
¹³ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Bone Neoplasms / genetics*
Bone Neoplasms / pathology
Bone Neoplasms / secondary
Breast Neoplasms / genetics*
Breast Neoplasms / pathology
Cadherins / genetics
Cell Line, Tumor
Female
Humans
Neoplasm Staging
Osteogenesis / genetics*
TOR Serine-Threonine Kinases / genetics
Tumor Microenvironment / genetics*

Substances

Cadherins
MTOR protein, human
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding