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Nat Commun. 2017 Feb 9;8:14344. doi: 10.1038/ncomms14344.

Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination.

Author information

1
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
2
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
3
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
4
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
5
Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
6
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
7
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Abstract

Metastasis-competent circulating tumour cells (CTCs) experience oxidative stress in the bloodstream, but their survival mechanisms are not well defined. Here, comparing single-cell RNA-Seq profiles of CTCs from breast, prostate and lung cancers, we observe consistent induction of β-globin (HBB), but not its partner α-globin (HBA). The tumour-specific origin of HBB is confirmed by sequence polymorphisms within human xenograft-derived CTCs in mouse models. Increased intracellular reactive oxygen species (ROS) in cultured breast CTCs triggers HBB induction, mediated through the transcriptional regulator KLF4. Depletion of HBB in CTC-derived cultures has minimal effects on primary tumour growth, but it greatly increases apoptosis following ROS exposure, and dramatically reduces CTC-derived lung metastases. These effects are reversed by the anti-oxidant N-Acetyl Cysteine. Conversely, overexpression of HBB is sufficient to suppress intracellular ROS within CTCs. Altogether, these observations suggest that β-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.

PMID:
28181495
PMCID:
PMC5321792
DOI:
10.1038/ncomms14344
[Indexed for MEDLINE]
Free PMC Article

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