Deciphering the interplay between circadian rhythms and metabolic preferences in colorectal cancer cells and 3D spheroids.

Aubert, Léo;Özkan, Kübra;Srhir, Sarah;Bruno, Philippine;Feron, Olivier;et.al.
(2023) Gordon Research Seminar: “Biological Timekeepers: Models, Mechanisms and Physiology” — Location: Bates College (17.June.2023)

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Abstract
While disruption of circadian rhythms has been associated with an increased risk of metabolic disorders, including cancer, much less is known about how alterations in clock machinery influence the progression of established tumors. The interplay between circadian rhythms and metabolism makes this question highly relevant considering the growing interest for tumor bioenergetics. We have previously documented that tumor acidosis shifts cancer cell metabolic preference from glucose to lipids, and that this rewiring significantly contributes to cancer progression. While acidosis is usually restricted to some tumor areas and may thus be spatially targeted, we now examined whether tackling the circadian clock machinery may impact on cancer metabolism and progression. For this purpose, we examined the spatiotemporal expression of circadian clock proteins and evaluated how drugs targeting them influence metabolism through the lens of the tumor microenvironment. We used colorectal cancer (CRC) cell lines adapted to acidic pH, as well as 3D spheroids that spontaneously recapitulate pH gradients observed in tumors. Using CRC clock reporter cells, we revealed significant alterations in circadian rhythms at acidic pH, with a global decrease in the expression of core clock components. We also performed spatial transcriptomics and time-course immunofluorescence studies in 3D CRC spheroids and documented a heterogeneous spatial distribution of key actors of the circadian clock machinery including BMAL1, CLOCK and PER2. Treatment with KL001, a stabilizer of CRY (a protein known to heterodimerize with PER2 to co-repress BMAL1), led to a dose-dependent lengthening of oscillation periods. In CRC spheroids, high dose KL001 exerted cytostatic effects while lower doses induced a redistribution of PER2 from the rim to the entire spheroids together with the re-oxygenation of the spheroid center. The latter observation was further supported by the capacity of KL001 to reduce the oxygen consumption rate in CRC cells as determined by Seahorse analysis. Finally, we highlighted additive and synergistic effects in 3D CRC spheroids when combining KL001 with drugs targeting lipid metabolism. Altogether, our data shed a new light on the tumor expression of clock genes and the possibility to impact cancer cell growth and lipid metabolism by pharmacologically modulating the activity of major regulators of circadian rhythms.
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Aubert, L., Özkan, K., Srhir, S., Bruno, P., Guilbaud, C., & Feron, O. (2023). Deciphering the interplay between circadian rhythms and metabolic preferences in colorectal cancer cells and 3D spheroids. Gordon Research Seminar: “Biological Timekeepers: Models, Mechanisms and Physiology”, Bates College. https://hdl.handle.net/2078.5/25310