title: The Greater Genomic Landscape: The Heterogeneous Evolution of Cancer.
abstract: Results have historically shown a broad plasticity in the origin of tumors and their functions, with significant heterogeneity observed in both morphologies and functional capabilities. Largely unknown, however, are the mechanisms by which these variations occur and how these events influence tumor formation and behavior. Contemporary views on the origin of tumors focus mainly on the role of particular sets of driver transformations, mutational or epigenetic, with the occurrence of the observed heterogeneity as an accidental byproduct of oncogenesis. As such, we present a hypothesis that tumors form due to heterogeneous adaptive selection in response to environmental stress through intrinsic genomic sampling mechanisms. Specifically, we propose that eukaryotic cells intrinsically explore their available genomic information, the greater genomic landscape (GGL), in response to stress under normal conditions, long before the formation of a cancerous lesion. Finally, considering the influence of chromatin heterogeneity on the GGL, we propose a new class of compounds, chromatin-protective therapies (CPT), which target the physical variations in chromatin topology. In this approach, CPTs reduce the overall information space available to limit the formation of tumors or the development of drug-resistant phenotypes. Cancer Res; 76(19); 5605-9. ©2016 AACR.
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Luay M
authors.initials: LM
authors.lastname: Almassalha
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Greta M
authors.initials: GM
authors.lastname: Bauer
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: John E
authors.initials: JE
authors.lastname: Chandler
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois.
authors.forename: Scott
authors.initials: S
authors.lastname: Gladstein
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. v-backman@northwestern.edu igalsz@northwestern.edu hkroy@bu.edu.
authors.forename: Igal
authors.initials: I
authors.lastname: Szleifer
authors.affiliation: Section of Gastroenterology, Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts. v-backman@northwestern.edu igalsz@northwestern.edu hkroy@bu.edu.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Roy
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois. v-backman@northwestern.edu igalsz@northwestern.edu hkroy@bu.edu.
authors.forename: Vadim
authors.initials: V
authors.lastname: Backman
mesh_terms: D002843:Chromatin / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D019143:Evolution, Molecular; D023281:Genomics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D002843:Chromatin