RNA-Seq of Single Prostate CTCs Implicates Noncanonical Wnt Signaling in Antiandrogen Resistance
By D. Miyamoto, Yu Zheng, Ben S. Wittner, Richard J Lee, Huili Zhu, Katherine T. Broderick, R. Desai, Douglas B. Fox, Brian W. Brannigan, Julie Trautwein and 13 more. Science, 2015
683 citations recorded by the source corpus.
Circulating signals of drug resistance Cancer drugs often lose their effectiveness because tumors acquire genetic changes that confer drug resistance. Ideally, patients would be switched to a different drug before tumor growth resumes, but this requires early knowledge of how resistance arose. Miyamoto et al. have developed a non-invasive method to spot resistance by sequencing RNA transcripts in single circulating tumor cells (CTCs) (see the Perspective by Nanus and Giannakakou). For example, in prostate cancer patients, drug resistance was triggered by activation of the Wnt signaling pathway. But CTCs are rare and fragile, and the technology needs further development before it is used in clinical practice. Science, this issue p. 1351; see also p. 1283 Analysis of circulating tumor cells from prostate cancer patients reveals a mechanism that contributes to treatment failure. [Also see Perspective by Nanus and Giannakakou] 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.
Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/362f024cdc3acaea9b195edbd11a7383f2240399
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Citations in the corpus
- Single-cell entropy for accurate estimation of differentiation potency from a cell's transcriptome (2017, methodology): “Attesting to its general nature and broad applicability, we compute and validate signalling entropy in over 7,000 single cells of variable degrees of differentiation potency and phenotypic plasticity, including time-course differentiation data, neoplastic cells and circulating tumour cells (CTCs).”
- EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS (2017, neutral): “Indeed, one already-published report demonstrates that CTCs isolated from prostate cancer patients can be harbingers of eventually acquired drug resistance, such as those carrying molecular changes that can confer resistance to androgen receptor antagonists (Miyamoto et al., 2015).”
- Liquid Biopsy: From Discovery to Clinical Application. (2021, methodology): “RNA-seq of single CTCs has been used in prostate cancer (20), breast cancer (21, 22), and pancreatic cancer (23) and led to the identification of prognostic signatures, metastatic drivers, and drug target and resistance mechanisms.”