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.

Biocruces Health Research Institute Barakaldo Spain

Campus Bio Medico University of Rome Rome Italy

Cancer Research Center CIBER ONC number CB16 12 00400 Salamanca Spain

Clinica Universidad de Navarra Centro de Investigacion Medica Aplicada CIBER ONC numbers CB16 12 00369 and CB16 12 00489 Pamplona Spain

Complejo Hospitalario de Navarra Pamplona Spain

Department of Clinical and Experimental Medicine Magna Graecia University Catanzaro Italy

Department of Hematooncology University Hospital of Ostrava Ostrava Czech Republic Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematooncology University Hospital of Ostrava Ostrava Czech Republic Faculty of Medicine University of Ostrava Ostrava Czech Republic Faculty of Science University of Ostrava Ostrava Czech Republic

Department of Hematooncology University Hospital of Ostrava Ostrava Czech Republic Faculty of Science University of Ostrava Ostrava Czech Republic

Department of Hematooncology University Hospital of Ostrava Ostrava Czech Republic Masaryk University Brno Czech Republic

Hospital Clínico Universitario Lozano Blesa Zaragoza Spain

Hospital Son Espases Palma Spain

Hospital Universitario 12 de Octubre Madrid Spain

Hospital Universitario Virgen de las Nieves Granada Spain

Masaryk University Brno Czech Republic

National Center for Cancer Care and Research Hamad Medical Corporation Doha Qatar

Translational Genomics Research Institute Phoenix AZ USA

University Hospital Brno Brno Czech Republic

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$a Garcés, Juan-Jose $u 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.

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$a Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination / $c JJ. Garcés, M. Simicek, M. Vicari, L. Brozova, L. Burgos, R. Bezdekova, D. Alignani, MJ. Calasanz, K. Growkova, I. Goicoechea, X. Agirre, L. Pour, F. Prosper, R. Rios, J. Martinez-Lopez, P. Millacoy, L. Palomera, R. Del Orbe, A. Perez-Montaña, S. Garate, L. Blanco, M. Lasa, P. Maiso, J. Flores-Montero, L. Sanoja-Flores, Z. Chyra, A. Vdovin, T. Sevcikova, T. Jelinek, C. Botta, H. El Omri, J. Keats, A. Orfao, R. Hajek, JF. San-Miguel, B. Paiva,

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$a 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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700    1_

$a Simicek, Michal $u Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic. Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. Faculty of Science, University of Ostrava, Ostrava, Czech Republic.

700    1_

$a Vicari, Marco $u Campus Bio-Medico University of Rome, Rome, Italy.

700    1_

$a Brozova, Lucie $u Masaryk University, Brno, Czech Republic.

700    1_

$a Burgos, Leire $u 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.

700    1_

$a Bezdekova, Renata $u University Hospital Brno, Brno, Czech Republic.

700    1_

$a Alignani, Diego $u 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.

700    1_

$a Calasanz, Maria-Jose $u 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.

700    1_

$a Growkova, Katerina $u Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic. Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. Faculty of Science, University of Ostrava, Ostrava, Czech Republic.

700    1_

$a Goicoechea, Ibai $u 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.

700    1_

$a Agirre, Xabier $u 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.

700    1_

$a Pour, Ludek $u University Hospital Brno, Brno, Czech Republic.

700    1_

$a Prosper, Felipe $u 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.

700    1_

$a Rios, Rafael $u Hospital Universitario Virgen de las Nieves, Granada, Spain.

700    1_

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700    1_

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700    1_

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700    1_

$a Del Orbe, Rafael $u Biocruces Health Research Institute, Barakaldo, Spain.

700    1_

$a Perez-Montaña, Albert $u Hospital Son Espases, Palma, Spain.

700    1_

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700    1_

$a Blanco, Laura $u 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.

700    1_

$a Lasa, Marta $u 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.

700    1_

$a Maiso, Patricia $u 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.

700    1_

$a Flores-Montero, Juan $u 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.

700    1_

$a Sanoja-Flores, Luzalba $u 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.

700    1_

$a Chyra, Zuzana $u Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic. Masaryk University, Brno, Czech Republic.

700    1_

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700    1_

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700    1_

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700    1_

$a Botta, Cirino $u Department of Clinical and Experimental Medicine, Magna Graecia University, Catanzaro, Italy.

700    1_

$a El Omri, Halima $u National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

700    1_

$a Keats, Jonathan $u Translational Genomics Research Institute, Phoenix, AZ, USA.

700    1_

$a Orfao, Alberto $u 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.

700    1_

$a Hajek, Roman $u Department of Hematooncology, University Hospital of Ostrava, Ostrava, Czech Republic. Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.

700    1_

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700    1_

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