Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination
Juan-Jose Garcés, Michal Simicek, Marco Vicari, Lucie Brozova, Leire Burgos, Renata Bezdekova, Diego Alignani, Maria-Jose Calasanz, Katerina Growkova, Ibai Goicoechea, Xabier Agirre, Ludek Pour, Felipe Prosper, Rafael Rios, Joaquin Martinez-Lopez, Pamela Millacoy, Luis Palomera, Rafael Del Orbe, Albert Perez-Montaña, Sonia Garate, Laura Blanco, Marta Lasa, Patricia Maiso, Juan Flores-Montero, Luzalba Sanoja-Flores, Zuzana Chyra, Alexander Vdovin, Tereza Sevcikova, Tomas Jelinek, Cirino Botta, Halima El Omri, Jonathan Keats, Alberto Orfao, Roman Hajek, Jesus F San-Miguel, Bruno Paiva
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.