Mimicking circadian dietary rhythms in 3D tumor spheroids to influence spatiotemporal fluctuations in cancer metabolism and optimize chronotherapeutic strategies

Details

Supervisors

Feron, Olivier

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Dietary regimens have recently emerged as promising strategies for reducing the risk of developing various diseases. Time-restricted feeding (TRF), in particular, has revealed some benefits in the prevention but also correction of cardiometabolic diseases and diabetes. These data sparked an interest for TRF in medical oncology, because of the necessary metabolic rewiring associated with cancer progression. Indeed, by altering the balance between feeding and fasting periods, TRF has the potential to alter the availability of nutrients and thereby to force cancer cells to become more dependent on specific metabolic pathways that may be therapeutically targeted. In this research project, we aimed to uncover and exploit such metabolic adaptations occurring in cancer cells in response to TRF by using 3D tumor spheroid models. For this purpose, spheroids were exposed alternately to feeding- and fasting-mimicking media, elaborated based on daily fluctuations in the plasma nutrient concentrations of the main fuels used by cancer cells. Two TRF protocols were considered: a 12h feeding/ 12h fasting protocol (TRF 12h) reflecting day/night fluctuations, and a 4h feeding/ 20h fasting (TRF 4h) scheme to study bona fide TRF. The impact was compared to an ad libitum (AL) condition (i.e., feeding-mimicking medium only), that represents conventional culturing methods. The spheroids were generated from cancer cells derived from distinct cancer types, namely FaDu (head and neck) and HT-29 (colorectal) cells. Our results revealed that while the growth and viability of 3D spheroids were globally maintained, a glucose and fatty acid metabolic rewiring, and consecutive associated alterations in the microenvironment, could be observed in response to the TRF protocols. Among the most prominent TRF-induced metabolic alterations, we found a reduction in glycolytic metabolism (during fasting periods), an enhanced glucose avidity (during the feeding periods) and a decreased de novo lipid biosynthesis together with a higher fatty acid uptake and storage. This latter result led us to identify a TRF-triggered increase in 3D spheroid sensitivity to ferroptosis induced by polyunsaturated fatty acid supplementation and the GPX4 inhibitor RSL3. Altogether, our results support the hypothesis that TRF may induce metabolic vulnerabilities in cancer cells that may be successfully targeted with ad hoc drugs.