Research in the Masri lab is aimed at understanding the relationship between disruption of circadian rhythms and tumorigenesis (Verlande and Masri, Trends in Endocrinology and Metabolism, 2019). The circadian clock sustains self-perpetuating oscillations with a 24-hour periodicity. These circadian (from the Latin words, circa diem, meaning‘about a day’) rhythms include sleep-wake cycles, feeding behavior, body temperature, endocrine oscillations and metabolic control. Disruptions in biological rhythms result in numerous physiological disorders, the consequences of which have been linked to several pathologies, including cancer. The molecular machinery that constitutes the circadian clock is comprised of two transcription factors, CLOCK and BMAL1, that heterodimerize and direct transcriptional activation of core clock genes and additional clock-controlled genes (CCGs), as shown below. Additionally, we have shown that the mammalian sirtuin SIRT6 is involved in the regulation of circadian transcription and metabolism (Masri et al., Cell 2014).
Genetic Disruption of the Clock and links to Cancer
The Masri lab is dissecting how genetic disruption of the circadian clock in mouse models alters tumorigenesis both at the level of initiation and disease progression. These studies are being carried out in genetically engineered mouse models (GEMMs) of cancer. We are currently examining how the circadian clock impinges on the stem cell niche, to determine if clock disruption deregulates stem cell homeostasis and potentially results in cancer initiation. These studies have very important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression. In addition, these studies provide novel insight into the potential for therapeutic targeting of the circadian clock for treatment of cancer.
Using a novel GEMM developed by the Masri lab, we are investigating how clock disruption accelerates colorectal cancer. This work is being carried out in vivo, as well as ex vivo using mouse intestinal organoids that model mini-gut structures in a 3D matrix. Images shown below represents WT and clock mutant organoids that develop into tumor spheres. Using these intestinal organoids, we investigate stemness potential, metabolic changes and inflammatory cues that shape the tumor microenvironment. Additionally, the Masri lab employs state-of-the-art technology including stable isotope metabolic tracing using metabolomics, RNA-sequencing, microbiome analysis using metagenomics, and whole organism metabolic phenotyping by indirect calorimetry.
Circadian Control of Tumor Metabolism – A systems view
We are elucidating the systemic crosstalk between tumors and peripheral tissues and how cancer cells are able to rewire circadian metabolism at a distance. This is based on our previous studies which reported a role of lung adenocarcinoma in distally rewiring circadian metabolism in the liver (Masri et al., Cell 2016). We are characterizing the biological consequences of tumor-dependent metabolic intermediates which may circulate in the blood. A major unanswered question is given the efflux of circulating tumor-dependent metabolites, can tumors repurpose metabolic intermediates by hijacking host cellular pathways for alternative energy production? We are currently utilizing new metabolic cage technology that depends on stable isotope sensors to determine consumption of candidate tumor-dependent metabolites in mouse models of cancer. Moreover, the fate of these tumor-dependent metabolites is being mapped in vivo to determine the metabolic pathways that are able to repurpose these building blocks into fuel for tumors. Importantly, we aim to identify key tumor-dependent metabolic intermediates and the host cellular pathways responsible for metabolic repurposing, as a means to establish novel therapeutic modalities for starving tumors.