title: Evolutionary scalpels for dissecting tumor ecosystems.
abstract: Amidst the growing literature on cancer genomics and intratumor heterogeneity, essential principles in evolutionary biology recur time and time again. Here we use these principles to guide the reader through major advances in cancer research, highlighting issues of "hit hard, hit early" treatment strategies, drug resistance, and metastasis. We distinguish between two frameworks for understanding heterogeneous tumors, both of which can inform treatment strategies: (1) The tumor as diverse ecosystem, a Darwinian population of sometimes-competing, sometimes-cooperating cells; (2) The tumor as tightly integrated, self-regulating organ, which may hijack developmental signals to restore functional heterogeneity after treatment. While the first framework dominates literature on cancer evolution, the second framework enjoys support as well. Throughout this review, we illustrate how mathematical models inform understanding of tumor progression and treatment outcomes. Connecting models to genomic data faces computational and technical hurdles, but high-throughput single-cell technologies show promise to clear these hurdles. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.
authors.affiliation: Department of Systems Biology, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address: dsr2131@columbia.edu.
authors.forename: Daniel I S
authors.initials: DIS
authors.lastname: Rosenbloom
authors.affiliation: Department of Systems Biology, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Pablo G
authors.initials: PG
authors.lastname: Camara
authors.affiliation: Department of Systems Biology, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Chu
authors.affiliation: Department of Systems Biology, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, 1130 St. Nicholas Avenue, New York, NY 10032, USA. Electronic address: rr2579@cumc.columbia.edu.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D015972:Gene Expression Regulation, Neoplastic; D056084:Genetic Fitness; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: Cancer evolution; Combination therapy; Drug resistance; Genomics; Intratumor heterogeneity; Mathematical modeling