title: Ancient hot and cold genes and chemotherapy resistance emergence.
abstract: We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.
authors.affiliation: Princeton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544;
authors.forename: Amy
authors.initials: A
authors.lastname: Wu
authors.affiliation: Department of Physics, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Qiucen
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Lambert
authors.affiliation: Moffitt Cancer Center, Tampa, FL 33612;
authors.forename: Zayar
authors.initials: Z
authors.lastname: Khin
authors.affiliation: Moffitt Cancer Center, Tampa, FL 33612;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
authors.affiliation: Department of Bioengineering, University of California, Santa Cruz, CA 95064;
authors.forename: Hyunsung John
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, University of California, Santa Cruz, CA 95064;
authors.forename: Nader
authors.initials: N
authors.lastname: Pourmand
authors.affiliation: The Biodesign Institute, Arizona State University, Tempe, AZ 85287;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bussey
authors.affiliation: Beyond Center for Fundamental Concepts in Science, Arizona State University, Tempe, AZ 85287;
authors.forename: Paul C W
authors.initials: PC
authors.lastname: Davies
authors.affiliation: Princeton Institute for the Science and Technology of Materials, Department of Electrical Engineering, Princeton University, Princeton, NJ 08544;
authors.forename: James C
authors.initials: JC
authors.lastname: Sturm
authors.affiliation: Department of Physics, Princeton University, Princeton, NJ 08544 austin@princeton.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Austin
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000737:chemistry; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D020128:Inhibitory Concentration 50; D008164:Luminescent Proteins / Q000378:metabolism; D044085:Microfluidics; D015233:Models, Statistical; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D000097573:Red Fluorescent Protein
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein
keywords: ancient genes; cancer; cold; emergence; hot