David Blask, MD, PhD

• Melatonin/Circadian Regulation and Light at Night Circadian Disruption of Cancer Growth

Tulane Cancer Center Program Member

For the past 35 years I have dedicated my research career to understanding the mechanisms by which the central circadian system of the brain regulates human breast cancer growth and metabolism via the nighttime circadian production of the pineal gland hormone melatonin.  Melatonin is arguably the most important output signal of the central circadian clock in the suprachiasmatic nucleus (SCN) and has very potent direct oncostatic actions on a variety of human cancer cells and xenografts including breast, prostate, colorectal, squamous cell head/neck, cervical, urothelial and mesenchymally-derived cancers such as leiomyosarcoma.  Using a unique tissue-isolated human cancer xenograft/nude rat model system developed in our laboratory, we discovered a highly novel pathway by which the nocturnal circadian melatonin signal inhibits human cancer growth in vivo.  This pathway involves the ability of melatonin to suppress cAMP-activated tumor uptake of dietary linoleic acid (LA), an essential omega-6 fatty acid, and its conversion to its mitogenic metabolite 13-hydroxyoctadecadienoic acid (13-HODE) as well as decreased tumor glucose uptake and lactate production (e.g., Warburg effect).  This results in a down-regulation in the activation of ERK1/2 and AKT signaling pathways leading to severely curtailed tumor growth at night while, in the absence of melatonin during the daytime, these mechanisms are fully active resulting a very high proliferative rate.  Circadian disruption/suppression of the nocturnal melatonin signal by exposure of tumor-bearing animals to light at night leads to constantly up-regulated LA uptake/metabolism and the Warburg effect and culminates in runaway tumor growth.  In studies paralleling those performed in our animal model, we have also demonstrated, by perfusing tissue-isolated human breast cancers with blood collected from human subjects during different times of the day and night, that the nocturnal circadian melatonin signal in adult female human subjects inhibits tumor metabolic signaling and proliferative activity.  Furthermore, exposure of human subjects to bright light at night suppresses the nocturnal circadian melatonin signal resulting in high, daytime-like rates of tumor metabolism and growth.  I am a Professor in the Dept. of Structural & Cellular Biology, Head of the Laboratory of Chrono-Neuroendocrine Oncology, and Associate Director of the Tulane Center for Circadian Biology in the Tulane University School of Medicine. I am also a member of the Tulane Cancer Center and Louisiana Cancer Research Consortium and the Tulane Center for Aging.  My work has been funded over the years by multiple RO1 grants from NIH/NCI, NIH/NCCAM, and NIEHS.