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

Yu Zheng, David T. Miyamoto, Ben S. Wittner, James P. Sullivan, Nicola Aceto, Nicole Vincent Jordan, Min Yu, Nezihi Murat Karabacak, Valentine Comaills, Robert Morris, Rushil Desai, Niyati Desai, Erin Emmons, John D. Milner, Richard J. Lee, Chin-Lee Wu, Lecia V. Sequist, Wilhelm Haas, David T. Ting, Mehmet Toner, Sridhar Ramaswamy, Shyamala Maheswaran () and Daniel A. Haber ()
Additional contact information
Yu Zheng: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
David T. Miyamoto: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Ben S. Wittner: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
James P. Sullivan: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Nicola Aceto: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Nicole Vincent Jordan: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Min Yu: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Nezihi Murat Karabacak: Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School
Valentine Comaills: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Robert Morris: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Rushil Desai: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Niyati Desai: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Erin Emmons: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
John D. Milner: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Richard J. Lee: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Chin-Lee Wu: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Lecia V. Sequist: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Wilhelm Haas: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
David T. Ting: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Mehmet Toner: Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School
Sridhar Ramaswamy: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Shyamala Maheswaran: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School
Daniel A. Haber: Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14344

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