Expression of the chemokine receptor CCR1 promotes the dissemination of multiple myeloma plasma cells <i>in vivo</i>
Mara N. Zeissig,
Duncan R. Hewett,
Vasilios Panagopoulos,
Krzysztof M. Mrozik,
L. Bik To,
Peter I. Croucher,
Andrew C.W. Zannettino,
Kate Vandyke
Affiliations
Mara N. Zeissig
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide
Duncan R. Hewett
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide
Vasilios Panagopoulos
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide
Krzysztof M. Mrozik
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide
L. Bik To
Department of Haematology, Royal Adelaide Hospital, Adelaide
Peter I. Croucher
Bone Biology Division, Garvan Institute of Medical Research, Sydney, Australia; St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney
Andrew C.W. Zannettino
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, Australia; Central Adelaide Local Health Network, Adelaide, Australia; Centre for Cancer Biology, University of South Australia, Adelaide
Kate Vandyke
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, Australia; Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide
Multiple myeloma (MM) disease progression is dependent on the ability of MM plasma cells (PC) to egress from the bone marrow (BM), enter the circulation and disseminate to distal BM sites. Expression of the chemokine CXCL12 by BM stromal cells is crucial for MM PC retention within the BM. However, the mechanisms which overcome CXCL12-mediated retention to enable dissemination are poorly understood. We have previously identified that treatment with the CCR1 ligand CCL3 inhibits the response to CXCL12 in MM cell lines, suggesting that CCL3/CCR1 signaling may enable egress of MM PC from the BM. Here, we demonstrated that CCR1 expression was an independent prognostic indicator in newly diagnosed MM patients. Furthermore, we showed that CCR1 is a crucial driver of dissemination in vivo, with CCR1 expression in the murine MM cell line 5TGM1 being associated with an increased incidence of bone and splenic disseminated tumors in C57BL/KaLwRij mice. Furthermore, we demonstrated that CCR1 knockout in the human myeloma cell line OPM2 resulted in a >95% reduction in circulating MM PC numbers and BM and splenic tumor dissemination following intratibial injection in NSG mice. Therapeutic targeting of CCR1 with the inhibitor CCX9588 significantly reduced OPM2 or RPMI-8226 dissemination in intratibial xenograft models. Collectively, our findings suggest a novel role for CCR1 as a critical driver of BM egress of MM PC during tumor dissemination. Furthermore, these data suggest that CCR1 may represent a potential therapeutic target for the prevention of MM tumor dissemination.
