@article{7371b80a8cc6444f8d06633eb7dd8eb4,
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.",
author = "Lawson, {Michelle A.} and McDonald, {Michelle M.} and Natasa Kovacic and Khoo, {Weng Hua} and Terry, {Rachael L.} and Jenny Down and Warren Kaplan and Julia Paton-Hough and Clair Fellows and Pettitt, {Jessica A.} and Dear, {T. Neil} and {Van Valckenborgh}, Els and Baldock, {Paul A.} and Rogers, {Michael J.} and Eaton, {Colby L.} and Karin Vanderkerken and Pettit, {Allison R.} and Quinn, {Julian M W} and Zannettino, {Andrew C W} and Phan, {Tri Giang} and Croucher, {Peter I.}",
note = "Funding Information: We thank A. Basten and R. Brink for critical reading of the manuscript and D. Rowe (University of Connecticut Health Center) for his kind gift of the pOBCol2.3GFPemd mice. We thank the MLC Flow Facility for cell sorting, the Small Animal Imaging Facility for intravital imaging, the Biological Testing Facility for animal husbandry at the Garvan Institute of Medical Research, and the UNSW Australia, Ramaciotti Centre for Gene Function Analysis for microarry analysis. P.I.C. is funded by Mrs Janice Gibson and the Ernest Heine Family Foundation, T.G.P. by an NHMRC Career Development Fellowship (1005097), M.M.M. by an International Bone and Mineral Society Gregory Mundy Fellowship, P.A.B. by an Australian Research Council Future Fellowship and E.V.V. by the FWO-VI and J.M.W.Q. by an NHMRC Project Grant (GNT1057706). This work was supported at least in part by a specialist programme grant from Leukaemia and Lymphoma Research, the OverMyr European Union Framework VII programme, the Cancer Council NSW (726), the Prostate Cancer Foundation of Australia and Movember, and the NHMRC (project grant 631484).",
year = "2015",
month = dec,
day = "3",
doi = "10.1038/ncomms9983",
language = "English",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}