Lena BrückerStefanie Kornelia BeckerVanessa MaisslGregory Harms...
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查看更多>>摘要：Primary cilia are microtubule-based cell organelles important for cellular communication.Since they are involved in the regulation of numerous signalling pathways,defects in cilia development or function are associated with genetic disorders,collectively called ciliopathies.Besides their ciliary functions,recent research has shown that several ciliary proteins are involved in the coordination of the actin cytoskeleton.Although ciliary and actin phenotypes are related,the exact nature of their interconnection remains incompletely understood.Here,we show that the protein BBS6,associated with the ciliopathy Bardet-Biedl syndrome,cooperates with the actin-bundling protein Fascin-1 in regulating filopodia and ciliary signalling.We found that loss of Bbs6affects filopodia length potentially via attenuated interaction with Fascin-1.Conversely,loss of Fascin-1 leads to a ciliary phenotype,subsequently affecting ciliary Wnt signalling,possibly in collaboration with BBS6.Our data shed light on how ciliary proteins are involved in actin regulations and provide new insight into the involvement of the actin regulator Fascin-1 in ciliogenesis and cilia-associated signalling.Advancing our knowledge of the complex regulations between primary cilia and actin dynamics is important to understand the pathogenic consequences of ciliopathies.
查看更多>>摘要：DNA methylation analysis has been applied to determine the primary site of cancer;however,robust and accurate prediction of cancer types with a minimum number of sites is still a significant scientific challenge.To build an accurate and robust cancer type prediction tool with a minimum number of DNA methylation sites,we internally benchmarked different DNA methylation site selection and ranking procedures,as well as different classification models.We used The Cancer Genome Atlas dataset(26 cancer types with 8296 samples)to train and test models and used an independent dataset(17 cancer types with 2738 samples)for model validation.A deep neural network model using a combined feature selection procedure(named MethyDeep)can predict 26 cancer types using 30 methylation sites with superior performance compared with the known methods for both primary and metastatic cancers in independent validation datasets.In conclusion,MethyDeep is an accurate and robust cancer type predictor with the minimum number of DNA methylation sites;it could help the cost-effective clarification of cancer of unknown primary patients and the liquid biopsy-based early screening of cancers.
查看更多>>摘要：Recent studies have demonstrated that cancer-associated adipocytes(CAAs)in the tumor microenvironment are involved in the malignant progression of breast cancer.However,the underlying mechanism of CAA formation and its effects on the development of breast cancer are still unknown.Here,we show that CSF2 is highly expressed in both CAAs and breast cancer cells.CSF2 promotes inflammatory phenotypic changes of adipocytes through the Stat3 signaling pathway,leading to the secretion of multiple cytokines and proteases,particularly C-X-C motif chemokine ligand 3(CXCL3).Adipocyte-derived CXCL3 binds to its specific receptor CXCR2 on breast cancer cells and activates the FAK pathway,enhancing the mesenchymal phenotype,migration,and invasion of breast cancer cells.In addition,a combination treatment targeting CSF2 and CXCR2 shows a synergistic inhibitory effect on adipocyte-induced lung metastasis of mouse 4T1 cells in vivo.These findings elucidate a novel mechanism of breast cancer metastasis and provide a potential therapeutic strategy for breast cancer metastasis.
查看更多>>摘要：The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pandemic has caused a global economic and health crisis.Recently,plasma levels of galectin-9(Gal-9),a β-galactoside-binding lectin involved in immune regulation and viral immunopatho-genesis,were reported to be elevated in the setting of severe COVID-19 disease.However,the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated.In this study,we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells(AECs),including immortalized AECs and primary AECs cultured at the air-liquid interface.Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an angiotensin-converting enzyme 2(ACE2)-dependent manner,enhancing the binding of the viral spike protein to ACE2.Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs,including the IL-6,IL-8,IL-17,EIF2,and TNFα signaling pathways.Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.
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