RNA-Seq of Single Prostate CTCs Implicates Noncanonical Wnt Signaling in Antiandrogen Resistance

Overview

Journal Science

Specialty Science

Date 2015 Sep 19

PMID 26383955

Citations 381

Authors

David T Miyamoto

Yu Zheng

Ben S Wittner

Richard J Lee

Huili Zhu

Katherine T Broderick

Rushil Desai

Douglas B Fox

Brian W Brannigan

Julie Trautwein

Kshitij S Arora

Niyati Desai

Douglas M Dahl

Lecia V Sequist

Matthew R Smith

Ravi Kapur

Chin-Lee Wu

Toshi Shioda

Sridhar Ramaswamy

David T Ting

Mehmet Toner

Shyamala Maheswaran

Daniel A Haber

Affiliations

Soon will be listed here.

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.

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