title: Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche.
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.
authors.affiliation: Department of Oncology, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.|Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lawson
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: McDonald
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Kovacic
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|School of Biotechnology and Biomolecular Sciences, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Weng
authors.initials: W
authors.lastname: Hua Khoo
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Terry
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Down
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.affiliation: Department of Oncology, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.|Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Paton-Hough
authors.affiliation: Department of Oncology, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.|Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
authors.forename: Clair
authors.initials: C
authors.lastname: Fellows
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Pettitt
authors.affiliation: South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Neil Dear
authors.affiliation: Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels 1090, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Baldock
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rogers
authors.affiliation: Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.|Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK.
authors.forename: Colby L
authors.initials: CL
authors.lastname: Eaton
authors.affiliation: Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels 1090, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Mater Research Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Woolloongabba, Queensland 4102, Australia.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Pettit
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Quinn
authors.affiliation: South Australian Health and Medical Research Institute, Adelaide, South Australia 5000, Australia.|School of Medical Sciences, University of Adelaide, Frome Road, Adelaide, South Australia 5000, Australia.
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Tri Giang
authors.initials: TG
authors.lastname: Phan
authors.affiliation: Garvan Institute of Medical Research, 384 Victoria Street, Sydney, New South Wales 2010, Australia.|St Vincent's Clinical School, Faculty of Medicine, UNSW Australia, Sydney, New South Wales 2010, Australia.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Croucher
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism*; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology*