Osteoclasts control reactivation of dormant myeloma cells by remodelling the endosteal niche
Open Access
- 3 December 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 6 (1), 8983
- https://doi.org/10.1038/ncomms9983
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.This publication has 65 references indexed in Scilit:
- GAS6 Receptor Status Is Associated with Dormancy and Bone Metastatic Tumor FormationPLOS ONE, 2013
- Endothelial and perivascular cells maintain haematopoietic stem cellsNature, 2012
- VCAM-1 Promotes Osteolytic Expansion of Indolent Bone Micrometastasis of Breast Cancer by Engaging α4β1-Positive Osteoclast ProgenitorsCancer Cell, 2011
- First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trialThe Lancet, 2010
- Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrowNature, 2009
- Analysis of histone 2B-GFP retention reveals slowly cycling hematopoietic stem cellsNature Biotechnology, 2008
- Live-animal tracking of individual haematopoietic stem/progenitor cells in their nicheNature, 2008
- GenePattern 2.0Nature Genetics, 2006
- Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancerCancer Cell, 2005
- Osteoclast differentiation and activationNature, 2003