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Nat Commun. 2015 Dec 3;6:8983. doi: 10.1038/ncomms9983.

Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche.

Author information

1
Department of Oncology, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
2
Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
3
Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
4
St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
5
School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, New South Wales 2010, Australia.
6
South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.
7
Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels 1090, Belgium.
8
Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
9
Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland 4102, Australia.
10
School of Medical Sciences, University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia.

Abstract

Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and repopulate the tumour. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and reactivation. In this study, we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state that is switched 'on' by engagement with bone-lining cells or osteoblasts, and switched 'off' by osteoclasts remodelling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy that targets dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

PMID:
26632274
PMCID:
PMC4686867
DOI:
10.1038/ncomms9983
[Indexed for MEDLINE]
Free PMC Article

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