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Science. 2015 Sep 18;349(6254):1351-6. doi: 10.1126/science.aab0917.

RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance.

Author information

  • 1Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 2Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
  • 3Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 4Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 5Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 6Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 7Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 8Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu.
  • 9Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu.

Abstract

Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.

Copyright © 2015, American Association for the Advancement of Science.

PMID:
26383955
[PubMed - indexed for MEDLINE]
PMCID:
PMC4872391
Free PMC Article
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