title: Highly variable cancer subpopulations that exhibit enhanced transcriptome variability and metastatic fitness.
abstract: Individual cells within a tumour can exhibit distinct genetic and molecular features. The impact of such diversification on metastatic potential is unknown. Here we identify clonal human breast cancer subpopulations that display different levels of morphological and molecular diversity. Highly variable subpopulations are more proficient at metastatic colonization and chemotherapeutic survival. Through single-cell RNA-sequencing, inter-cell transcript expression variability is identified as a defining feature of the highly variable subpopulations that leads to protein-level variation. Furthermore, we identify high variability in the spliceosomal machinery gene set. Engineered variable expression of the spliceosomal gene SNRNP40 promotes metastasis, attributable to cells with low expression. Clinically, low SNRNP40 expression is associated with metastatic relapse. Our findings reveal transcriptomic variability generation as a mechanism by which cancer subpopulations can diversify gene expression states, which may allow for enhanced fitness under changing environmental pressures encountered during cancer progression.
authors.affiliation: Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York 10065, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York 10065, USA.
authors.forename: Mitsukuni
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York 10065, USA.
authors.forename: Hani
authors.initials: H
authors.lastname: Goodarzi
authors.affiliation: Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York 10065, USA.
authors.forename: Sohail F
authors.initials: SF
authors.lastname: Tavazoie
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D012008:Recurrence; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics* / Q000378:metabolism; D059010:Single-Cell Analysis; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D017411:Ribonucleoproteins, Small Nuclear; C000610373:SNRNP40 protein, human; D004317:Doxorubicin; D017239:Paclitaxel