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

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 ?-globin (HBB), but not its partner ?-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 ?-globin is selectively deregulated in cancer cells, mediating a cytoprotective effect during blood-borne metastasis.

SUBMITTER: Zheng Y

PROVIDER: S-EPMC5321792 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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

Zheng Yu Y Miyamoto David T DT Wittner Ben S BS Sullivan James P JP Aceto Nicola N Jordan Nicole Vincent NV Yu Min M Karabacak Nezihi Murat NM Comaills Valentine V Morris Robert R Desai Rushil R Desai Niyati N Emmons Erin E Milner John D JD Lee Richard J RJ Wu Chin-Lee CL Sequist Lecia V LV Haas Wilhelm W Ting David T DT Toner Mehmet M Ramaswamy Sridhar S Maheswaran Shyamala S Haber Daniel A DA

Nature communications 20170209

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 s ...[more]

PMID: 28181495

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Dataset Information

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

Publications

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

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