The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability

Hai Wang; Lin Tian; Jun Liu; Amit Goldstein; Igor Bado; Weijie Zhang; Benjamin R Arenkiel; Zonghai Li; Meng Yang; Shiyu Du; Hong Zhao; David R Rowley; Stephen T C Wong; Zbigniew Gugala; Xiang H-F Zhang

doi:10.1016/j.ccell.2018.10.002

The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability

Cancer Cell. 2018 Nov 12;34(5):823-839.e7. doi: 10.1016/j.ccell.2018.10.002.

Authors

Hai Wang¹, Lin Tian², Jun Liu¹, Amit Goldstein¹, Igor Bado¹, Weijie Zhang¹, Benjamin R Arenkiel³, Zonghai Li⁴, Meng Yang⁵, Shiyu Du⁶, Hong Zhao⁷, David R Rowley⁸, Stephen T C Wong⁹, Zbigniew Gugala¹⁰, Xiang H-F Zhang¹¹

Affiliations

¹ 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.
² 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.
³ Department of Human and Molecular Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; McNair Medical Institute, Baylor College of Medicine, BCM600, One Baylor Plaza, Houston, TX 77030, USA.
⁴ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, P.R. China.
⁵ Department of General Surgery, China-Japan Friendship Hospital, Beijing 100029, China.
⁶ Department of Gastroenterology, China-Japan Friendship Hospital, Beijing 100029, China.
⁷ Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, 6670 Bertner Avenue, 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 Cellular 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; Department of Systems Medicine and Bioengineering, Houston Methodist Research Institute, 6670 Bertner Avenue, Houston, TX 77030, USA.
¹⁰ Department of Orthopaedic Surgery & Rehabilitation, University of Texas Medical Branch, Galveston, TX 77555, USA.
¹¹ 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, BCM600, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: xiangz@bcm.edu.

Abstract

The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.

Keywords: bone metastasis; breast cancer; calcium signaling; drug discovery or repositioning; gap junctions; microenvironment; micrometastasis; prostate cancer; the osteogenic niche; therapeutic responses.

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

3T3 Cells
Animals
Antineoplastic Agents / pharmacology*
Arsenic Trioxide / pharmacology*
Benzamides / pharmacology*
Bone Neoplasms / pathology*
Bone Neoplasms / prevention & control
Bone Neoplasms / secondary*
Breast Neoplasms / pathology*
Breast Neoplasms / therapy
Calcium / metabolism
Calcium Signaling / physiology
Cell Line, Tumor
Cell Proliferation / physiology
Connexin 43 / metabolism
Everolimus / pharmacology
Female
Humans
MCF-7 Cells
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Nude
Osteogenesis / physiology*
Protein Kinase Inhibitors / pharmacology*
Pyrazoles / pharmacology*
RAW 264.7 Cells
Tumor Microenvironment / physiology
U937 Cells

Substances

Antineoplastic Agents
Benzamides
Connexin 43
GJA1 protein, human
Protein Kinase Inhibitors
Pyrazoles
Everolimus
danusertib
Arsenic Trioxide
Calcium

Abstract

Publication types

MeSH terms

Substances

Grants and funding