Expression of β-globin by cancer cells promotes cell survival during blood-borne dissemination.
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.
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Yu
Y
Zheng
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
David T
DT
Miyamoto
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Ben S
0000-0001-5657-9849
BS
Wittner
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
James P
JP
Sullivan
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nicola
N
Aceto
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
Nicole Vincent
NV
Jordan
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Min
M
Yu
Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nezihi Murat
NM
Karabacak
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Valentine
V
Comaills
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Robert
R
Morris
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Rushil
R
Desai
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Niyati
N
Desai
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Erin
E
Emmons
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
John D
JD
Milner
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Richard J
RJ
Lee
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Chin-Lee
CL
Wu
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Lecia V
LV
Sequist
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Wilhelm
W
Haas
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
David T
DT
Ting
Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Mehmet
M
Toner
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Sridhar
S
Ramaswamy
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Shyamala
S
Maheswaran
Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.|Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Daniel A
DA
Haber
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D019610:Cytoprotection / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D009360:Neoplastic Cells, Circulating / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013312:Stress, Physiological; D015854:Up-Regulation / Q000235:genetics; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism
D000975:Antioxidants; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017382:Reactive Oxygen Species; D055544:beta-Globins