SCARB1 in extracellular vesicles promotes NPC metastasis by co-regulating M1 and M2 macrophage function.

Distant metastasis is currently the main factor affecting the prognosis of nasopharyngeal carcinoma (NPC), and understanding the mechanisms of metastasis and identifying reliable therapeutic targets are critical for improving prognosis and achieving clinical translation. Macrophages, as important immune cells in the tumor microenvironment (TME), have been shown to regulate metastasis. And extracellular vesicles (EVs) secreted by stromal cells and tumor cells play the important role in intercellular communication in the tumor microenvironment. However, the role of NPC-EVs on macrophages and their function in regulating macrophages to affect metastasis has not been fully clarified. In this study, we report that NPC-EVs can be uptake by macrophages and alter macrophage polarization, for the first time, we identified the genes implicated in these regulatory functions: SCARB1, HAAO, and CYP1B1. Moreover, we found that SCARB1 was positively associated with metastasis and poor prognosis of NPC. Interestingly, we found that SCARB1-rich EVs promoted M1 macrophages ferroptosis to decrease M1 macrophages infiltration by upregulating the HAAO level while decreasing phagocytosis of M2 macrophages by upregulating the CYP1B1 level. Finally, we identified the SCARB1-binding gene KLF9, which is involved in the transcription of HAAO and CYP1B1. Our findings showed that SCARB1-EVs promoted metastasis by co-regulating M1 and M2 macrophage function. The related mechanism will provide a new therapeutic strategy to help patients with NPC improve their prognosis.

Adherence to 24-h movement guidelines and cognitive difficulties in adolescents.

BACKGROUND: Studies have identified sleep, screen time, and physical activity as independent risk factors for cognitive impairment in adolescents. However, little is known about how these factors interact to contribute to cognitive difficulties. This study aimed to investigate the association between 24-h movement guidelines and cognitive difficulties in adolescents. METHODS: Data from the 2019 Youth Risk Behaviour Surveillance was used for analysis. Participants self-reported their screen time, sleep, and physical activity levels, and cognitive difficulty was assessed using a standardized protocol with a binary response (Yes or No). Logistic regression analysis was used to evaluate the association between 24-h movement behaviours and cognitive difficulty, with results reported as the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: After controlling for covariates (e.g., sex, age), compared to adolescents not adhering to none of the 24-h movement guidelines, adhering to the screen time (OR = 1.68, 95%CI: 1.37-2.05) and sleep guidelines (OR = 1.32, 95%CI: 1.08-1.61) were more likely to report no cognitive difficulties in adolescents, respectively. Adhering to all the 24-h movement guidelines was also likely to increase the odds of reporting no cognitive difficulties (OR = 3.38, 95%: 2.15-5.30). CONCLUSIONS: The study findings suggest that promoting better 24-h movement behaviours could be an effective approach to reducing cognitive difficulties in adolescents. Future studies should use improved study designs to confirm or refute these results.

AMPK-mTOR-Mediated Activation of Autophagy Promotes Formation of Dormant Polyploid Giant Cancer Cells.

Dormant cancer cells that survive anticancer therapy can lead to cancer recurrence and disseminated metastases that prove fatal in most cases. Recently, specific dormant polyploid giant cancer cells (PGCC) have drawn our attention because of their association with the clinical risk of nasopharyngeal carcinoma (NPC) recurrence, as demonstrated by previous clinical data. In this study, we report the biological properties of PGCC, including mitochondrial alterations, and reveal that autophagy is a critical mechanism of PGCC induction. Moreover, pharmacologic or genetic inhibition of autophagy greatly impaired PGCC formation, significantly suppressing metastasis and improving survival in a mouse model. Mechanistically, chemotherapeutic drugs partly damaged mitochondria, which then produced low ATP levels and activated autophagy via the AMPK-mTOR pathway to promote PGCC formation. Analysis of the transcriptional and epigenetic landscape of PGCC revealed overexpression of RIPK1, and the scaffolding function of RIPK1 was required for AMPK-mTOR pathway-induced PGCC survival. High numbers of PGCCs correlated with shorter recurrence time and worse survival outcomes in patients with NPC. Collectively, these findings suggest a therapeutic approach of targeting dormant PGCCs in cancer. SIGNIFICANCE: Pretreatment with an autophagy inhibitor before chemotherapy could prevent formation of therapy-induced dormant polyploid giant cancer cells, thereby reducing recurrence and metastasis of nasopharyngeal carcinoma.