01
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, characterized by poor survival rates despite current treatments such as surgery, radiotherapy, and chemotherapy. The researchers aimed to investigate the role of circadian rhythms in GBM progression and the mechanisms by which daily signals from the host regulate tumor growth. They focused on glucocorticoids, hormones that are secreted rhythmically, and their interaction with GBM's intrinsic circadian rhythms.
The researchers first demonstrated that GBM cells possess intrinsic circadian rhythms regulated by clock genes such as Bmal1 and Per2. Using both human and mouse GBM models, they showed that glucocorticoids influence tumor growth in a time-of-day-dependent manner. Specifically, glucocorticoids promote tumor growth when administered during the morning, when Bmal1 expression peaks, and suppress growth during the evening, when Per2 expression is at its highest. This effect depends on glucocorticoid receptor (GR) signaling, as silencing GR eliminated the time-dependent effects of glucocorticoids on tumor growth.
Next, the researchers explored the synchronization between GBM tumors and the host’s central circadian clock. They found that GBM tumors act as peripheral circadian oscillators, aligning their rhythms with the host’s circadian signals through GR-mediated pathways. Furthermore, disrupting circadian rhythms in the host slowed tumor growth and disease progression, highlighting the critical role of circadian synchrony in tumor biology.
In conclusion, this study establishes that circadian rhythms drive GBM progression and that glucocorticoid signaling plays a central role in synchronizing tumor growth to the host’s daily cycles. These findings underscore the importance of circadian timing in GBM treatment and suggest that targeting glucocorticoid signaling or incorporating chronotherapy could enhance therapeutic outcomes. This work provides a framework for future studies exploring time-based interventions in cancer treatment.
DOI: 10.1101/2024.05.03.592418
02
The cGAS-STING pathway is a critical DNA-sensing mechanism in mammalian cells, responsible for detecting cytoplasmic DNA and activating innate immune responses. While its role in inducing autophagy for pathogen clearance has been well established, whether this pathway also modulates lysosome biogenesis and function remains unclear. The researchers aimed to investigate how the cGAS-STING pathway regulates lysosomal activity and its significance in cellular immunity.
The researchers first demonstrated that activation of the cGAS-STING pathway upregulates lysosomal biogenesis independently of TBK1, a downstream kinase. They observed that STING activation promotes the nuclear translocation of transcription factor TFEB, a master regulator of lysosome biogenesis. This translocation occurs via a unique mechanism involving STING-induced lipidation of GABARAP, an autophagy-related protein, on single-membrane vesicles. The lipidated GABARAP sequesters the folliculin complex, inhibiting its interaction with Rag GTPases, which in turn prevents mTORC1-mediated phosphorylation of TFEB and allows its nuclear activation.
Next, the researchers explored the functional significance of STING-induced lysosomal biogenesis. They found that it enhances the clearance of cytoplasmic DNA, bacteria, and viruses. For example, STING activation significantly improved the degradation of bacterial DNA in lysosomes and restricted the intracellular replication of Salmonella Typhimurium. Similarly, the pathway facilitated antiviral defense against herpes simplex virus-1 (HSV-1), demonstrating its broader role in innate immune responses.
In conclusion, this study reveals a previously unrecognized function of the cGAS-STING pathway in promoting lysosomal biogenesis through TFEB activation. These findings not only advance the understanding of lysosomal regulation in immunity but also highlight potential therapeutic targets for enhancing host defense mechanisms against infections and related diseases. This work provides a foundation for future studies on the interplay between autophagy, lysosomes, and immune signaling.
DOI: 10.1016/j.immuni.2024.11.017
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