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RESEARCH PRODUCT

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

Felipe ProsperLuzalba Sanoja-floresDiego AlignaniIbai GoicoecheaJuan José GarcésJesús F. San-miguelPatricia MaisoTereza SevcikovaSonia GarateLeire BurgosPamela MillacoyHalima El OmriRoman HájekAlberto OrfaoKaterina GrowkovaAlexander VdovinBruno PaivaMarco VicariAlbert Pérez-montañaXabier AgirreJoaquin Martinez-lopezRafael RiosLuis PalomeraRenata BezdekovaMarta LasaJuan Flores-monteroCirino BottaRafael Del OrbeTomas JelinekMichal SimicekZuzana ChyraLucie BrozovaJonathan J KeatsLudek PourMaria-jose CalasanzLaura Blanco

subject

0301 basic medicineCancer ResearchEpithelial-Mesenchymal TransitionTranscription GeneticGene ExpressionBiologycirculating tumor cell03 medical and health sciences0302 clinical medicineCirculating tumor cellBone MarrowCell MovementCancer stem cellCell Line TumorTumor MicroenvironmentmedicineHumansHypoxiaMultiple myelomaCell ProliferationInflammationGene knockdownliquid biopsyCD44CENPFHematologyNeoplastic Cells CirculatingPrognosismedicine.disease3. Good healthmultiple myeloma030104 developmental biologymedicine.anatomical_structureOncologyCell culture030220 oncology & carcinogenesisNeoplastic Stem CellsCancer researchbiology.proteinBone marrow

description

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.

yearjournalcountryeditionlanguage
2020-01-01
10.1038/s41375-019-0588-4http://hdl.handle.net/10261/223080