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Multiple myeloma gammopathies

Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination

Abstract

The reason why a few myeloma cells egress from the bone marrow (BM) into peripheral blood (PB) remains unknown. Here, we investigated molecular hallmarks of circulating tumor cells (CTCs) to identify the events leading to myeloma trafficking into the bloodstream. After using next-generation flow to isolate matched CTCs and BM tumor cells from 32 patients, we found high correlation in gene expression at single-cell and bulk levels (r ≥ 0.94, P = 10−16), with only 55 genes differentially expressed between CTCs and BM tumor cells. CTCs overexpressed genes involved in inflammation, hypoxia, or epithelial–mesenchymal transition, whereas genes related with proliferation were downregulated in CTCs. The cancer stem cell marker CD44 was overexpressed in CTCs, and its knockdown significantly reduced migration of MM cells towards SDF1-α and their adhesion to fibronectin. Approximately half (29/55) of genes differentially expressed in CTCs were prognostic in patients with newly-diagnosed myeloma (n = 553; CoMMpass). In a multivariate analysis including the R-ISS, overexpression of CENPF and LGALS1 was significantly associated with inferior survival. Altogether, these results help understanding the presence of CTCs in PB and suggest that hypoxic BM niches together with a pro-inflammatory microenvironment induce an arrest in proliferation, forcing tumor cells to circulate in PB and seek other BM niches to continue growing.

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Acknowledgements

We would like to thank to the patients and their families who participated in this study.

Funding

This study was supported by the Centro de Investigación Biomédica en Red —Área de Oncología— del Instituto de Salud Carlos III (CIBERONC; CB16/12/00369, CB16/12/00489, and CB16/12/00400), Cancer Research UK, FCAECC and AIRC under the Accelerator Award Programme, Instituto de Salud Carlos III and Asociación Española Contra el Cáncer by ERA-NET TRANSCAN-2 Programme (AC17/00101), the Black Swan Research Initiative of the International Myeloma Foundation, the European Research Council (ERC) 2015 Starting Grant (MYELOMANEXT, 680200), the Czech Science Foundation through Project No. 19-25354Y, the European Regional Development Fund—Project ENOCH (No. CZ.02.1.01/0.0/0.0/16_019/0000868), and the Ministry of Health of the Czech Republic (15-29667A).

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RH, JFSM, and BP conceived the idea and designed the study protocol; XA, LP, FP, RR, JML, PM, LP, RdO, APM, JFM, LSF, TJ, HEO, JK, AO, RH, and JFSM provided study material and patients; LB and BP analyzed flow cytometry data; DA, SG, and RB performed cell sorting; JJG, LB, KG, and ZC extracted the samples and processed the arrays; MV, DA, and SG executed the single-cell RNA-seq experiment; JJG, MV, LB, IG, TS, and CB did/supervised the bioinformatics processing and JJG, MS, MV, KG, and BP analyzed and interpreted data; in vitro experiments were performed by KG, AV, LB, ML, and PM. JJG, MS, MV, and BP wrote the paper and all authors reviewed and approved the paper.

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Correspondence to Bruno Paiva.

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Garcés, JJ., Simicek, M., Vicari, M. et al. Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination. Leukemia 34, 589–603 (2020). https://doi.org/10.1038/s41375-019-0588-4

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