转移
基因沉默
生物
癌症研究
乳腺癌
癌症
转录组
肿瘤进展
基因
基因表达
遗传学
作者
Niccolò Roda,Andrea Cossa,Roman Hillje,Andrea Tirelli,Federica Ruscitto,Stefano Cheloni,Chiara Priami,Alberto Dalmasso,Valentina Gambino,Giada Blandano,Andrea Polazzi,Paolo Falvo,Elena Gatti,Luca Mazzarella,Lucilla Luzi,Enrica Migliaccio,Pier Giuseppe Pelicci
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-05-03
卷期号:83 (13): 2155-2170
被引量:3
标识
DOI:10.1158/0008-5472.can-22-2717
摘要
Abstract Metastatic breast cancer has a poor prognosis and is largely considered incurable. A better understanding of the molecular determinants of breast cancer metastasis could facilitate development of improved prevention and treatment strategies. We used lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during breast cancer metastasis and showed that metastases derive from rare prometastatic clones that are underrepresented in primary tumors. Both low clonal fitness and high metastatic potential were independent of clonal origin. Differential expression and classification analyses revealed that the prometastatic phenotype was acquired by rare cells characterized by the concomitant hyperactivation of extracellular matrix remodeling and dsRNA-IFN signaling pathways. Notably, genetic silencing of key genes in these pathways (KCNQ1OT1 or IFI6, respectively) significantly impaired migration in vitro and metastasis in vivo, with marginal effects on cell proliferation and tumor growth. Gene expression signatures derived from the identified prometastatic genes predict metastatic progression in patients with breast cancer, independently of known prognostic factors. This study elucidates previously unknown mechanisms of breast cancer metastasis and provides prognostic predictors and therapeutic targets for metastasis prevention. Significance: Transcriptional lineage tracing coupled with single-cell transcriptomics defined the transcriptional programs underlying metastatic progression in breast cancer, identifying prognostic signatures and prevention strategies.
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