Journal
SCIENCE
Volume 349, Issue 6254, Pages 1351-1356Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aab0917
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Funding
- Prostate Cancer Foundation
- Charles Evans Foundation
- Department of Defense
- Stand Up to Cancer
- Howard Hughes Medical Institute
- National Institute of Biomedical Imaging and Bioengineering (NIBIB)
- NIH [EB008047]
- NCI [2RO1CA129933]
- National Cancer Institute, NCI
- Federal Share Program and Income
- Affymetrix, Inc.
- Mazzone Program-Dana-Farber Harvard Cancer Center
- Burroughs Wellcome Fund
- Massachusetts General Hospital-Johnson & Johnson Center for Excellence in CTC Technologies
- Janssen LLC.
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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.
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