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Visual experience orthogonalizes visual cortical stimulus responses via population code transformation.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-30 DOI: 10.1016/j.celrep.2025.115235
Samuel W Failor, Matteo Carandini, Kenneth D Harris
{"title":"Visual experience orthogonalizes visual cortical stimulus responses via population code transformation.","authors":"Samuel W Failor, Matteo Carandini, Kenneth D Harris","doi":"10.1016/j.celrep.2025.115235","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115235","url":null,"abstract":"<p><p>Sensory and behavioral experience can alter visual cortical stimulus coding, but the precise form of this plasticity is unclear. We measured orientation tuning in 4,000-neuron populations of mouse V1 before and after training on a visuomotor task. Changes to single-cell tuning curves appeared complex, including development of asymmetries and of multiple peaks. Nevertheless, these complex tuning curve transformations can be explained by a simple equation: a convex transformation suppressing responses to task stimuli specifically in cells responding at intermediate levels. The strength of the transformation varies across trials, suggesting a dynamic circuit mechanism rather than static synaptic plasticity. The transformation results in sparsening and orthogonalization of population codes for task stimuli. It cannot improve the performance of an optimal stimulus decoder, which is already perfect even for naive codes, but it improves the performance of a suboptimal decoder model with inductive bias as might be found in downstream readout circuits.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115235"},"PeriodicalIF":7.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143070741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A central role for acetylcholine in entorhinal cortex function and dysfunction with age in humans and mice.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-30 DOI: 10.1016/j.celrep.2025.115249
Mala R Ananth, John D Gardus, Chuan Huang, Nikhil Palekar, Mark Slifstein, Laszlo Zaborszky, Ramin V Parsey, David A Talmage, Christine DeLorenzo, Lorna W Role
{"title":"A central role for acetylcholine in entorhinal cortex function and dysfunction with age in humans and mice.","authors":"Mala R Ananth, John D Gardus, Chuan Huang, Nikhil Palekar, Mark Slifstein, Laszlo Zaborszky, Ramin V Parsey, David A Talmage, Christine DeLorenzo, Lorna W Role","doi":"10.1016/j.celrep.2025.115249","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115249","url":null,"abstract":"<p><p>Structural and functional changes in the entorhinal cortex (EC) are among the earliest signs of cognitive aging. Here, we ask whether a compromised cholinergic system influences early EC impairments and plays a primary role in EC cognition. We evaluated the relationship between loss of integrity of cholinergic inputs to the EC and cognitive deficits in otherwise healthy humans and mice. Using in vivo imaging (PET/MRI) in older humans and high-resolution imaging in wild-type mice and mice with genetic susceptibility to Alzheimer's disease pathology, we establish that loss of cholinergic input to the EC is, in fact, an early feature in cognitive aging. Through mechanistic studies in mice, we find a central role for EC-projecting cholinergic neurons in the expression of EC-related behaviors. Our data demonstrate that alterations to the cholinergic EC are an early, conserved feature of cognitive aging across species and may serve as an early predictor of cognitive status.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115249"},"PeriodicalIF":7.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-30 DOI: 10.1016/j.celrep.2025.115251
Min Chen, Yang Li, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Lin-Jing Yan, Shan Li, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo
{"title":"Exercise-induced adipokine Nrg4 alleviates MASLD by disrupting hepatic cGAS-STING signaling.","authors":"Min Chen, Yang Li, Jie-Ying Zhu, Wang-Jing Mu, Hong-Yang Luo, Lin-Jing Yan, Shan Li, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo","doi":"10.1016/j.celrep.2025.115251","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115251","url":null,"abstract":"<p><p>Exercise is an effective non-pharmacological strategy for ameliorating metabolic dysfunction-associated steatotic liver disease (MASLD). Neuregulin-4 (Nrg4) is an adipokine with a potential role in metabolic homeostasis. Previous findings have shown that Nrg4 is upregulated by exercise and that Nrg4 reduces hepatic steatosis, but the underlying mechanism is not fully understood. Here, we show that adipose Nrg4 is transactivated by Pparγ in response to exercise in mice. Adeno-associated virus (AAV)-mediated knockdown of adipose Nrg4 as well as hepatocyte-specific knockout of Erbb4 (Nrg4 receptor) impair exercise-mediated alleviation of MASLD in mice. Conversely, AAV-mediated overexpression of adipose Nrg4 mitigates MASLD in mice in synergy with exercise. Mechanistically, Nrg4/Erbb4/AKT signaling promotes cyclic guanosine monophosphate-AMP synthase (cGAS) phosphorylation to blunt its enzyme activity, thereby inhibiting cGAS-STING pathway-mediated inflammation and steatosis in hepatocytes. Thus, Nrg4 functions as an exercise-induced adipokine that participates in adipose-liver tissue communication to counteract MASLD.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115251"},"PeriodicalIF":7.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pde4b-regulated cAMP signaling pathway in the AUDGABA-S1TrSst circuit underlies acute-stress-induced anxiety-like behavior.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-30 DOI: 10.1016/j.celrep.2025.115253
Zhi-Xin Xiao, Xiao-Ya Wang, Nan Zhou, Xue-Tong Yi, Xiao-Qi Zhang, Qi-Lin Wu, Zhuo Li, Xia Zhang, Hua-Min Xu, Xu-Feng Xu
{"title":"Pde4b-regulated cAMP signaling pathway in the AUD<sup>GABA</sup>-S1Tr<sup>Sst</sup> circuit underlies acute-stress-induced anxiety-like behavior.","authors":"Zhi-Xin Xiao, Xiao-Ya Wang, Nan Zhou, Xue-Tong Yi, Xiao-Qi Zhang, Qi-Lin Wu, Zhuo Li, Xia Zhang, Hua-Min Xu, Xu-Feng Xu","doi":"10.1016/j.celrep.2025.115253","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115253","url":null,"abstract":"<p><p>Acute-stress-induced anxiety helps animals avoid danger, but the neural and molecular mechanisms controlling this behavior remain largely elusive. Here, we find that acute physical stress activates many neurons in the primary somatosensory cortex, trunk region (S1Tr). Single-cell sequencing reveals that the S1Tr c-fos-positive neurons activated by acute stress are largely GABAergic somatostatin (Sst) neurons. These S1Tr<sup>Sst</sup> neurons desensitize during subsequent anxiety-like behavior tests. Inhibiting or inducing apoptosis of S1Tr<sup>Sst</sup> neurons mimics acute-stress effects and induces anxiety, while activating these neurons reduces acute-stress-induced anxiety. S1Tr<sup>Sst</sup> cells receive inputs from secondary auditory cortex, dorsal area (AUD) GABAergic neurons to modulate this anxiety. Spatial transcriptome sequencing and targeted Pde4b protein knockdown show that acute stress reduces Pde4b-regulated cAMP signaling in AUD<sup>GABA</sup>-S1Tr<sup>Sst</sup> projections, leading to decreased S1Tr<sup>Sst</sup> neuron activity in subsequent behavioral tests. Our study reports a neural and molecular mechanism for acute-stress-induced anxiety, providing a basis for treating anxiety disorders.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115253"},"PeriodicalIF":7.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
G3BP1 ribonucleoprotein complexes regulate focal adhesion protein mobility and cell migration.
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-29 DOI: 10.1016/j.celrep.2025.115237
Liana C Boraas, Mengwei Hu, Pieter Martino, Lauren Thornton, Charles E Vejnar, Gang Zhen, Longhui Zeng, Dylan M Parker, Andy L Cox, Antonio J Giraldez, Xiaolei Su, Christine Mayr, Siyuan Wang, Stefania Nicoli
{"title":"G3BP1 ribonucleoprotein complexes regulate focal adhesion protein mobility and cell migration.","authors":"Liana C Boraas, Mengwei Hu, Pieter Martino, Lauren Thornton, Charles E Vejnar, Gang Zhen, Longhui Zeng, Dylan M Parker, Andy L Cox, Antonio J Giraldez, Xiaolei Su, Christine Mayr, Siyuan Wang, Stefania Nicoli","doi":"10.1016/j.celrep.2025.115237","DOIUrl":"https://doi.org/10.1016/j.celrep.2025.115237","url":null,"abstract":"<p><p>The subcellular localization of mRNAs plays a pivotal role in biological processes, including cell migration. For instance, β-actin mRNA and its associated RNA-binding protein (RBP), ZBP1/IGF2BP1, are recruited to focal adhesions (FAs) to support localized β-actin synthesis, crucial for cell migration. However, whether other mRNAs and RBPs also localize at FAs remains unclear. Here, we identify hundreds of mRNAs that are enriched at FAs (FA-mRNAs). FA-mRNAs share characteristics with stress granule (SG) mRNAs and are found in ribonucleoprotein (RNP) complexes with the SG RBP. Mechanistically, G3BP1 binds to FA proteins in an RNA-dependent manner, and its RNA-binding and dimerization domains, essential for G3BP1 to form RNPs in SG, are required for FA localization and cell migration. We find that G3BP1 RNPs promote cell speed by enhancing FA protein mobility and FA size. These findings suggest a previously unappreciated role for G3BP1 RNPs in regulating FA function under non-stress conditions.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 2","pages":"115237"},"PeriodicalIF":7.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual-nuclease single-cell lineage tracing by Cas9 and Cas12a. Cas9和Cas12a的双核酸酶单细胞谱系追踪。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-28 Epub Date: 2024-12-24 DOI: 10.1016/j.celrep.2024.115105
Cheng Chen, Yuanxin Liao, Miao Zhu, Li Wang, Xinran Yu, Meishi Li, Guangdun Peng
{"title":"Dual-nuclease single-cell lineage tracing by Cas9 and Cas12a.","authors":"Cheng Chen, Yuanxin Liao, Miao Zhu, Li Wang, Xinran Yu, Meishi Li, Guangdun Peng","doi":"10.1016/j.celrep.2024.115105","DOIUrl":"10.1016/j.celrep.2024.115105","url":null,"abstract":"<p><p>Single-cell lineage tracing based on CRISPR-Cas9 gene editing enables the simultaneous linkage of cell states and lineage history at a high resolution. Despite its immense potential in resolving the cell fate determination and genealogy within an organism, existing implementations of this technology suffer from limitations in recording capabilities and considerable barcode dropout. Here, we introduce DuTracer, a versatile tool that utilizes two orthogonal gene editing systems to record cell lineage history at single-cell resolution in an inducible manner. DuTracer shows the ability to enhance lineage recording with minimized target dropouts and potentially deeper tree depths. Applying DuTracer in mouse embryoid bodies and neuromesodermal organoids illustrates the lineage relationship of different cell types and proposes potential lineage-biased molecular drivers, showcased by identifying transcription factor Foxb1 as a modulator in the cell fate determination of neuromesodermal progenitors. Collectively, DuTracer facilitates the precise and regulatory interrogation of cellular lineages of complex biological processes.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115105"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Microenvironmental β-TrCP negates amino acid transport to trigger CD8+ T cell exhaustion in human non-small cell lung cancer. 微环境β-TrCP在人非小细胞肺癌中抑制氨基酸转运触发CD8+ T细胞衰竭。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-03 DOI: 10.1016/j.celrep.2024.115128
Ge Li, Zhenke Wen, Sidong Xiong
{"title":"Microenvironmental β-TrCP negates amino acid transport to trigger CD8<sup>+</sup> T cell exhaustion in human non-small cell lung cancer.","authors":"Ge Li, Zhenke Wen, Sidong Xiong","doi":"10.1016/j.celrep.2024.115128","DOIUrl":"10.1016/j.celrep.2024.115128","url":null,"abstract":"<p><p>CD8<sup>+</sup> T cell exhaustion (Tex) has been widely acknowledged in human cancer, while the underlying mechanisms remain unclear. Here, we demonstrate that reduced amino acid (aa) metabolism and mTOR inactivation are accountable for Tex in human non-small cell lung cancer (NSCLC). NSCLC cells impede the T cell-intrinsic transcription of SLC7A5 and SLC38A1, disrupting aa transport and consequently leading to mTOR inactivation. Further, the ubiquitination of YAP1 protein is the basis for NSCLC-mediated transcriptional inhibition of aa transporters. Mechanistically, NSCLC cells transfer β-TrCP-containing exosomes into T cells, inducing YAP1 ubiquitination and Tex. Consequently, inhibiting cancer-associated β-TrCP effectively restores the anti-tumor immune response of CD8<sup>+</sup> T cells and curtails tumor growth in NSCLC patient-derived organoids. Together, our findings highlight a β-TrCP-dependent mechanism in steering intrinsic metabolic adaptation and CD8<sup>+</sup> Tex, emphasizing microenvironmental β-TrCP as an immune checkpoint for therapeutic exploration against human NSCLC.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115128"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Isolation and structure of broad SIV-neutralizing antibodies reveal a proximal helical MPER epitope recognized by a rhesus multi-donor class. 广泛siv中和抗体的分离和结构揭示了恒河猴多供体类识别的近端螺旋MPER表位。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-09 DOI: 10.1016/j.celrep.2024.115163
Jason Gorman, Renguang Du, Yen-Ting Lai, Mohammed S Ahmadi, Hannah A D King, Kaimei Song, Kimberly Manalang, Christopher A Gonelli, Chaim A Schramm, Cheng Cheng, Richard Nguyen, David Ambrozak, Aliaksandr Druz, Chen-Hsiang Shen, Yongping Yang, Daniel C Douek, Peter D Kwong, Mario Roederer, Rosemarie D Mason
{"title":"Isolation and structure of broad SIV-neutralizing antibodies reveal a proximal helical MPER epitope recognized by a rhesus multi-donor class.","authors":"Jason Gorman, Renguang Du, Yen-Ting Lai, Mohammed S Ahmadi, Hannah A D King, Kaimei Song, Kimberly Manalang, Christopher A Gonelli, Chaim A Schramm, Cheng Cheng, Richard Nguyen, David Ambrozak, Aliaksandr Druz, Chen-Hsiang Shen, Yongping Yang, Daniel C Douek, Peter D Kwong, Mario Roederer, Rosemarie D Mason","doi":"10.1016/j.celrep.2024.115163","DOIUrl":"10.1016/j.celrep.2024.115163","url":null,"abstract":"<p><p>The membrane-proximal external region (MPER) of the HIV-1 envelope is a target for broadly neutralizing antibodies (bnAbs), and vaccine-elicited MPER-directed antibodies have recently been reported from a human clinical trial. In this study, we sought to identify MPER-directed nAbs in simian immunodeficiency virus (SIV)-infected rhesus macaques. We isolated four lineages of SIV MPER-directed nAbs from two SIV-infected macaques. The nAbs displayed low potency but up to 90% breadth on a 20-strain SIV panel. Crystal structures of representative nAbs in complex with SIV MPER peptides revealed the SIV antibodies to bind a helical epitope at the N-terminal (proximal) region of the MPER, defining a reproducible multi-donor class encompassing all four lineages. HIV-1 comparison showed that this class of SIV MPER-directed antibodies targets a helical region overlapping that targeted by human vaccine-elicited ones. Thus, a prevalent and reproducible class of SIV bnAbs recognizes an epitope similar to that recently observed in an HIV-1-vaccine trial.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115163"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis. 非典型肝雄激素受体通过PGC1α/ERRα/线粒体轴介导雌性小鼠胰高血糖素敏感性。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-09 DOI: 10.1016/j.celrep.2024.115188
Jie Chen, Yuanyuan Wu, Wanyu Hao, Jia You, Lianfeng Wu
{"title":"Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis.","authors":"Jie Chen, Yuanyuan Wu, Wanyu Hao, Jia You, Lianfeng Wu","doi":"10.1016/j.celrep.2024.115188","DOIUrl":"10.1016/j.celrep.2024.115188","url":null,"abstract":"<p><p>Glucagon has recently been found to modulate liver fat content, in addition to its role in regulating gluconeogenesis. However, the precise mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver remain poorly understood. By employing chemical and genetic approaches, we demonstrate that inhibiting the androgen receptor (AR) impairs the ability of glucagon to stimulate gluconeogenesis and lipid catabolism in primary hepatocytes and female mice. Notably, AR expression in the liver of female mice is up to three times higher than that in their male littermates, accounting for the more pronounced response to glucagon in females. Mechanistically, hepatic AR promotes energy metabolism and enhances lipid breakdown for liver glucose production in response to glucagon treatment through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)/estrogen-related receptor alpha (ERRα)-mitochondria axis. Overall, our findings highlight the crucial role of hepatic AR in mediating glucagon signaling and the sexual dimorphism in hepatic glucagon sensitivity.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115188"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142962009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression. amp激活的蛋白激酶的缺失会损害转移,并通过ROS清除或异位CD36表达来挽救。
IF 7.5 1区 生物学
Cell reports Pub Date : 2025-01-28 Epub Date: 2025-01-10 DOI: 10.1016/j.celrep.2024.115183
Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay
{"title":"Deletion of AMP-activated protein kinase impairs metastasis and is rescued by ROS scavenging or ectopic CD36 expression.","authors":"Gopalakrishnan Ramakrishnan, Alexander R Terry, Veronique Nogueira, Ahmed Magdy, Nissim Hay","doi":"10.1016/j.celrep.2024.115183","DOIUrl":"10.1016/j.celrep.2024.115183","url":null,"abstract":"<p><p>AMPK's role in tumor initiation and progression is controversial. Here, we provide genetic evidence that AMPK is required for metastasis in mouse models of breast cancer. In a mouse model of spontaneous breast cancer metastasis, the deletion of AMPK before and after tumor onset decreased breast cancer metastasis, and similar results were obtained after AMPK deletion in breast cancer cell lines. The deletion of AMPK induces reactive oxygen species (ROS) levels in vitro and lipid oxidation in vivo, which likely impede metastasis. Indeed, antioxidants restore the ability of AMPK-deficient tumors to metastasize. By inhibiting acetyl-coenzyme A (CoA) carboxylases 1 and 2, AMPK maintains NADPH levels by reducing NADPH consumption in fatty acid synthesis and increasing NADPH generation via fatty acid oxidation, thus increasing the dependency on auxotrophic fatty acids. Consistently, AMPK is required for the expression of the fatty acid transporter CD36 in tumors, and ectopic expression of CD36 in AMPK-deficient cells restored their ability to metastasize.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 1","pages":"115183"},"PeriodicalIF":7.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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