title: Circadian Rhythm Disruption Promotes Lung Tumorigenesis.
abstract: Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Thales
authors.initials: T
authors.lastname: Papagiannakopoulos
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Bauer
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Heimann
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Lakshmipriya
authors.initials: L
authors.lastname: Subbaraj
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Bartlebaugh
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D065150:Cellular Reprogramming; D002940:Circadian Rhythm / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D020179:Jet Lag Syndrome / Q000150:complications; D008168:Lung / Q000473:pathology*; D008175:Lung Neoplasms / Q000150:complications / Q000473:pathology; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D056950:Period Circadian Proteins / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
chemical_list: D056950:Period Circadian Proteins; D016271:Proto-Oncogene Proteins c-myc; D005973:Glutamine; D005947:Glucose
keywords: CRISPR; circadian rhythms; jet lag; lung cancer; physiology