RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance
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- 18 September 2015
- journal article
- other
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 349 (6254), 1351-1356
- https://doi.org/10.1126/science.aab0917
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.Keywords
Funding Information
- NIH (EB008047)
- Department of Defense
- Howard Hughes Medical Institute
- National Cancer Institute
- NCI (2RO1CA129933)
- National Institute of Biomedical Imaging and Bioengineering (NIBIB)
- Burroughs Wellcome Fund
- Prostate Cancer Foundation
- Johnson & Johnson
- Massachusetts General Hospital
- Stand Up To Cancer
- Charles Evans Foundation
- Federal Share Program and Income
- Affymetrix, Inc.
- Mazzone Program–Dana-Farber Harvard Cancer Center
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