title: Non-Darwinian dynamics in therapy-induced cancer drug resistance.
abstract: The development of drug resistance, the prime cause of failure in cancer therapy, is commonly explained by the selection of resistant mutant cancer cells. However, dynamic non-genetic heterogeneity of clonal cell populations continuously produces metastable phenotypic variants (persisters), some of which represent stem-like states that confer resistance. Even without genetic mutations, Darwinian selection can expand these resistant variants, which would explain the invariably rapid emergence of stem-like resistant cells. Here, by using quantitative measurements and modelling, we show that appearance of multidrug resistance in HL60 leukemic cells following treatment with vincristine is not explained by Darwinian selection but by Lamarckian induction. Single-cell longitudinal monitoring confirms the induction of multidrug resistance in individual cells. Associated transcriptome changes indicate a lasting stress response consistent with a drug-induced switch between high-dimensional cancer attractors. Resistance induction correlates with Wnt pathway upregulation and is suppressed by β-catenin knockdown, revealing a new opportunity for early therapeutic intervention against the development of drug resistance.
authors.affiliation: Institute for Systems Biology, Seattle WA 98109, USA.|Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Angela Oliveira
authors.initials: AO
authors.lastname: Pisco
authors.affiliation: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Brock
authors.affiliation: Institute for Systems Biology, Seattle WA 98109, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta AB T2N 1N4, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, CH-1015 Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Moor
authors.affiliation: Institute for Systems Biology, Seattle WA 98109, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta AB T2N 1N4, Canada.
authors.forename: Mitra
authors.initials: M
authors.lastname: Mojtahedi
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Dean
authors.initials: D
authors.lastname: Jackson
authors.affiliation: Institute for Systems Biology, Seattle WA 98109, USA.|Institute for Biocomplexity and Informatics, University of Calgary, Alberta AB T2N 1N4, Canada.
authors.forename: Sui
authors.initials: S
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D018922:HL-60 Cells; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012641:Selection, Genetic; D059010:Single-Cell Analysis; D059467:Transcriptome; D014750:Vincristine / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D034741:RNA, Small Interfering; D051176:beta Catenin; D014750:Vincristine
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