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

Science. 2015 Sep 18;349(6254):1351-6. doi: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use*
  • Animals
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Male
  • Mice
  • Neoplastic Cells, Circulating / drug effects
  • Neoplastic Cells, Circulating / metabolism*
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Phenylthiohydantoin / therapeutic use
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA Splicing
  • Receptors, Androgen / genetics*
  • Sequence Analysis, RNA / methods
  • Signal Transduction
  • Single-Cell Analysis / methods
  • Transcriptome
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*
  • Wnt-5a Protein
  • Xenograft Model Antitumor Assays

Substances

  • Androgen Antagonists
  • MDV 3100
  • Proto-Oncogene Proteins
  • Receptors, Androgen
  • WNT5A protein, human
  • Wnt Proteins
  • Wnt-5a Protein
  • Phenylthiohydantoin

Associated data

  • GEO/GSE67980