Long Term Goals: The first objective of this proposal is to identify and characterize the disruption of metabolic circadian rhythm and emergence of a new rhythmic metabolic program that oncogenes may introduce in cancer, and to study this effect in mouse models of lung cancer. The second objective is to prepare Brian Altman, Ph.D., under the mentorship of Dr. Chi Dang at the University of Pennsylvania, to acquire the skills necessary to transition to an independent academic research position. Brian will be trained in the fields of cancer metabolism and circadian rhythm through acquisition of new research skills, coursework on presentation and communication skills, coursework on preparing for and undertaking an academic job search, seminars on responsible research conduct, and attendance and presentation at national conferences. These will prepare Brian to transition to a career as an independent academic investigator. Background: Circadian rhythms in mammals are 24 hour cycles that govern cellular metabolism. While many cancers have disrupted circadian rhythms, there is little understanding of the implications of this disruption on cancer cell metabolism and growth. Better understanding of oncogenes in disrupting and changing the circadian metabolic cycle could aid in developing strategies to time treatment of for increased efficacy and reduced toxicity. We have previously shown that the MYC oncogene, which is involved in at least 50% of human cancers, can disrupt the machinery of circadian rhythm in cell culture and dramatically alter metabolic oscillation, possibly towards a new and more rapid program. Therefore, I hypothesize that the oncogenic expression of the Myc oncogene shifts the circadian metabolic cycle towards a highly efficient and rapid program that can be identified in several mouse models of lung cancer.
Specific Aims / Study Design: (1) To characterize the metabolic cycle induced by Myc using novel imaging techniques. (2) To study the role of Myc overexpression in the disruption of circadian rhythm and metabolism in a mouse model of lung cancer. (3) To study the role of the putative tumor suppressor gene MNT in disruption of circadian oscillation in a mouse lung model. To pursue these aims, I will use cell lines representing three tissue types to study the oscillation of metabolic processes with or without the Myc oncogene. Next, I will use a genetic mouse model of lung cancer to study Myc in disruption of circadian rhythm and metabolic oscillation. Finally, I will use cell lines and a mous model to study the effect of loss of MNT on circadian rhythm and metabolism. The mentored portion of my work will require me to learn complex metabolic imaging techniques, study the role of Myc in normal lung tissue, and use the exciting new CRISPR genetic deletion technology to study MNT loss in cell lines, all of which require the acquisition of new skills. I will carry this research forward in my independent phase to expand my studies of cell metabolism to include oscillation of biomass accumulation, and study Myc overexpression and MNT in mouse models of lung cancer.
The metabolism of all mammals goes through daily cycles that are known as circadian rhythms, and many cancers have disrupted or absent circadian rhythms, but the reason for this and its importance for tumor biology and growth are not well understood. This proposal aims to study the role of the common oncogene MYC in disrupting the circadian oscillation of cancer metabolism and endowing cancer cells with a new and more rapid metabolic program, which may help them grow faster and more efficiently. These studies will then be extended to several different mouse models of lung cancer to understand the importance of circadian rhythm disruption for cancer development and growth in a model of a disease that is still the leading cause of cancer deaths in the United States today.
|Bu, Yiwen; Yoshida, Akihiro; Chitnis, Nilesh et al. (2018) A PERK-miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival. Nat Cell Biol 20:104-115|
|Krishnaiah, Saikumari Y; Wu, Gang; Altman, Brian J et al. (2017) Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism. Cell Metab 25:961-974.e4|
|Altman, Brian J; Hsieh, Annie L; Gouw, Arvin M et al. (2017) Correspondence: Oncogenic MYC persistently upregulates the molecular clock component REV-ERB?. Nat Commun 8:14862|