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Leukemia. 2019 Oct 8. doi: 10.1038/s41375-019-0588-4. [Epub ahead of print]

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

Author information

1
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369 and CB16/12/00489, Pamplona, Spain.
2
Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic.
3
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
4
Faculty of Science, University of Ostrava, Ostrava, Czech Republic.
5
Campus Bio-Medico University of Rome, Rome, Italy.
6
Masaryk University, Brno, Czech Republic.
7
University Hospital Brno, Brno, Czech Republic.
8
Hospital Universitario Virgen de las Nieves, Granada, Spain.
9
Hospital Universitario 12 de Octubre, Madrid, Spain.
10
Complejo Hospitalario de Navarra, Pamplona, Spain.
11
Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain.
12
Biocruces Health Research Institute, Barakaldo, Spain.
13
Hospital Son Espases, Palma, Spain.
14
Cancer Research Center (IBMCC-CSIC/USAL-IBSAL), Cytometry Service (NUCLEUS) and Department of Medicine, University of Salamanca (USAL), , CIBER-ONC number CB16/12/00400, Salamanca, Spain.
15
Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy.
16
National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.
17
Translational Genomics Research Institute, Phoenix, AZ, USA.
18
Clinica Universidad de Navarra, Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC numbers CB16/12/00369 and CB16/12/00489, Pamplona, Spain. bpaiva@unav.es.

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.

PMID:
31595039
DOI:
10.1038/s41375-019-0588-4

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