title: Quantifying intrinsic and extrinsic control of single-cell fates in cancer and stem/progenitor cell pedigrees with competing risks analysis.
abstract: The molecular control of cell fate and behaviour is a central theme in biology. Inherent heterogeneity within cell populations requires that control of cell fate is studied at the single-cell level. Time-lapse imaging and single-cell tracking are powerful technologies for acquiring cell lifetime data, allowing quantification of how cell-intrinsic and extrinsic factors control single-cell fates over time. However, cell lifetime data contain complex features. Competing cell fates, censoring, and the possible inter-dependence of competing fates, currently present challenges to modelling cell lifetime data. Thus far such features are largely ignored, resulting in loss of data and introducing a source of bias. Here we show that competing risks and concordance statistics, previously applied to clinical data and the study of genetic influences on life events in twins, respectively, can be used to quantify intrinsic and extrinsic control of single-cell fates. Using these statistics we demonstrate that 1) breast cancer cell fate after chemotherapy is dependent on p53 genotype; 2) granulocyte macrophage progenitors and their differentiated progeny have concordant fates; and 3) cytokines promote self-renewal of cardiac mesenchymal stem cells by symmetric divisions. Therefore, competing risks and concordance statistics provide a robust and unbiased approach for evaluating hypotheses at the single-cell level.
authors.affiliation: Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia.|Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.|Australian Research Council Special Research Initiative in Stem Cell Science - Stem Cells, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Cornwell
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: S Auf
authors.initials: SA
authors.lastname: der Mauer
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.|McMaster Stem Cell and Cancer Research Institute, Michael G DeGroote School of Medicine, Hamilton, Ontario, Canada.|Murdoch Children's Research Institute, The Royal Children's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Motazedian
authors.affiliation: Cell Systems Dynamics, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Schroeder
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.|McMaster Stem Cell and Cancer Research Institute, Michael G DeGroote School of Medicine, Hamilton, Ontario, Canada.|Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8N 3Z5, Canada.
authors.forename: J S
authors.initials: JS
authors.lastname: Draper
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.|Australian Research Council Special Research Initiative in Stem Cell Science - Stem Cells, Australia.|St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
authors.forename: R P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: Graduate School of Biomedical Engineering, University of New South Wales, Sydney, NSW 2052, Australia.|Australian Research Council Special Research Initiative in Stem Cell Science - Stem Cells, Australia.
authors.forename: R E
authors.initials: RE
authors.lastname: Nordon
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics*; D058948:Cell Tracking / Q000379:methods / Q000706:statistics & numerical data*; D016207:Cytokines / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D055014:Granulocyte-Macrophage Progenitor Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D059010:Single-Cell Analysis / Q000379:methods / Q000706:statistics & numerical data*; D059008:Time-Lapse Imaging; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin