{"entity":{"id":"paper-labrecque-mcrpc-phenotypes-jci-2019","kind":"paper","name":"Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer","aka":[],"tldr":"Deep profiling of treatment-resistant prostate cancers found five distinct kinds rather than the two the field had assumed, and gave a 26-gene signature to tell them apart.","summary":"Deep phenotypic characterisation of castration-resistant prostate cancer metastases and patient-derived xenograft lines was carried out using whole-genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. The analyses revealed five phenotypes based on expression of well-characterised androgen receptor or neuroendocrine genes: androgen receptor-high tumours, androgen receptor-low tumours, amphicrine tumours composed of cells co-expressing androgen receptor and neuroendocrine genes, double-negative tumours, and tumours with small cell or neuroendocrine gene expression without androgen receptor activity. REST activity, which suppresses neuroendocrine gene expression, was lost in the amphicrine and small cell or neuroendocrine xenograft models, and knockdown experiments showed that attenuated REST activity drives the amphicrine phenotype but is not sufficient for conversion to the small cell or neuroendocrine phenotype. A subtype of double-negative tumours with squamous differentiation was identified, and a 26-gene transcriptional signature distinguishing the five phenotypes was generated.","asOf":"2026-09-25","links":[{"label":"Labrecque et al., J Clin Invest 2019: five phenotypes of treatment-refractory metastatic castration-resistant prostate cancer defined by androgen receptor and neuroendocrine gene expression","url":"https://doi.org/10.1172/JCI128212"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/31361600/"}],"tags":[],"related":[],"cancers":["prostate","prostate-mcrpc","prostate-nepc"],"sections":[],"technologies":["rna-seq","histopathology-ihc"],"targets":["androgen-receptor","ascl1"],"drugs":[],"companies":[],"institutions":[],"pathways":["lineage-plasticity-neuroendocrine","ar-signaling","transcription-addiction"],"terms":["histologic-transformation","castration-resistance","resistance"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["jci"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Investigation","year":2019,"doi":"10.1172/JCI128212","pmid":"31361600","authors":"Labrecque MP, Coleman IM, Brown LG, et al.","paperType":"basic","findings":["Five phenotypes of castration-resistant disease rather than two: androgen receptor-high, androgen receptor-low, amphicrine, double-negative and small cell or neuroendocrine.","Loss of REST activity drives the amphicrine phenotype but is not sufficient for small cell conversion.","A double-negative subtype with squamous differentiation.","A 26-gene transcriptional signature distinguishing the phenotypes."],"whatItMeans":"It gives the field a vocabulary for the states between androgen receptor-driven adenocarcinoma and small cell carcinoma, which matters because those in-between tumours are the ones most likely to be mismanaged as ordinary castration-resistant disease.","caveats":["Research metastases and patient-derived xenografts, not a prospective patient cohort.","The signature needs bulk RNA, which is rarely available from a routine metastatic biopsy.","No treatment is selected by phenotype today."],"changedPractice":false},"route":"/key-papers/paper-labrecque-mcrpc-phenotypes-jci-2019/","neighbours":{"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-nepc","kind":"cancer","name":"Neuroendocrine and small-cell prostate cancer","route":"/cancers/prostate-nepc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"}],"target":[{"id":"androgen-receptor","kind":"target","name":"Androgen receptor","route":"/targets/androgen-receptor/"},{"id":"ascl1","kind":"target","name":"ASCL1","route":"/targets/ascl1/"}],"pathway":[{"id":"ar-signaling","kind":"pathway","name":"Androgen receptor signalling","route":"/pathways/ar-signaling/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"term":[{"id":"castration-resistance","kind":"term","name":"Castration-resistant prostate cancer (CRPC)","route":"/terms/castration-resistance/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"histologic-transformation","kind":"term","name":"Histologic transformation","route":"/terms/histologic-transformation/"}],"journal":[{"id":"jci","kind":"journal","name":"Journal of Clinical Investigation","route":"/journals/jci/"}]}}