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

Michelle A. Lawson, Michelle M. McDonald, Natasa Kovacic, Weng Hua Khoo, Rachael L. Terry, Jenny Down, Warren Kaplan, Julia Paton-Hough, Clair Fellows, Jessica A. Pettitt, T. Neil Dear, Els Van Valckenborgh, Paul A. Baldock, Michael J. Rogers, Colby L. Eaton, Karin Vanderkerken, Allison R. Pettit, Julian M. W. Quinn, Andrew C. W. Zannettino, Tri Giang Phan () and Peter I. Croucher ()
Additional contact information
Michelle A. Lawson: University of Sheffield Medical School, University of Sheffield
Michelle M. McDonald: Garvan Institute of Medical Research
Natasa Kovacic: Garvan Institute of Medical Research
Weng Hua Khoo: Garvan Institute of Medical Research
Rachael L. Terry: Garvan Institute of Medical Research
Jenny Down: Garvan Institute of Medical Research
Warren Kaplan: Garvan Institute of Medical Research
Julia Paton-Hough: University of Sheffield Medical School, University of Sheffield
Clair Fellows: University of Sheffield Medical School, University of Sheffield
Jessica A. Pettitt: Garvan Institute of Medical Research
T. Neil Dear: South Australian Health and Medical Research Institute
Els Van Valckenborgh: Vrije Universiteit Brussel
Paul A. Baldock: Garvan Institute of Medical Research
Michael J. Rogers: Garvan Institute of Medical Research
Colby L. Eaton: Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield
Karin Vanderkerken: Vrije Universiteit Brussel
Allison R. Pettit: Mater Research Institute, The University of Queensland, Translational Research Institute
Julian M. W. Quinn: Garvan Institute of Medical Research
Andrew C. W. Zannettino: South Australian Health and Medical Research Institute
Tri Giang Phan: Garvan Institute of Medical Research
Peter I. Croucher: Garvan Institute of Medical Research

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9983

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