Signal Transduction and Targeted Therapy最新文献

{"title":"Pre-metastatic niche: formation, characteristics and therapeutic implication","authors":"Yuhang Wang, Jiachi Jia, Fuqi Wang, Yingshuai Fang, Yabing Yang, Quanbo Zhou, Weitang Yuan, Xiaoming Gu, Junhong Hu, Shuaixi Yang","doi":"10.1038/s41392-024-01937-7","DOIUrl":"https://doi.org/10.1038/s41392-024-01937-7","url":null,"abstract":"<p>Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding genetics, sex and signaling: Implications of sex-dependent APOE4-neutrophil-microglia interactions for Alzheimer’s and tauopathies","authors":"Natja Haag, Juliane Bremer, Hans Zempel","doi":"10.1038/s41392-024-01967-1","DOIUrl":"https://doi.org/10.1038/s41392-024-01967-1","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A systematic framework for understanding the microbiome in human health and disease: from basic principles to clinical translation","authors":"Ziqi Ma, Tao Zuo, Norbert Frey, Ashraf Yusuf Rangrez","doi":"10.1038/s41392-024-01946-6","DOIUrl":"https://doi.org/10.1038/s41392-024-01946-6","url":null,"abstract":"<p>The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the ‘innate and adaptive genomes’, which enhance genetic and evolutionary comprehension of the human genome. The ‘germ-free syndrome’ challenges the traditional ‘microbes as pathogens’ view, advocating for the necessity of microbes for health. The ‘slave tissue’ concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. ‘Acquired microbial immunity’ positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The ‘homeostatic reprogramming hypothesis’ integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The ‘cell-microbe co-ecology model’ elucidates the symbiotic regulation affecting cellular balance, while the ‘meta-host model’ broadens the host definition to include symbiotic microbes. The ‘health-illness conversion model’ encapsulates the innate and adaptive genomes’ interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell exome sequencing reveals polyclonal seeding and TRPS1 mutations in colon cancer metastasis","authors":"Jianqiang Cai, Weilong Zhang, Yalan Lu, Wenjie Liu, Haitao Zhou, Mei Liu, Xinyu Bi, Jianmei Liu, Jinghua Chen, Yanjiang Yin, Yiqiao Deng, Zhiwen Luo, Yi Yang, Qichen Chen, Xiao Chen, Zheng Xu, Yueyang Zhang, Chaoling Wu, Qizhao Long, Chunyuan Huang, Changjian Yan, Yan Liu, Lei Guo, Weihua Li, Pei Yuan, Yucheng Jiao, Wei Song, Xiaobing Wang, Zhen Huang, Jianming Ying, Hong Zhao","doi":"10.1038/s41392-024-01960-8","DOIUrl":"https://doi.org/10.1038/s41392-024-01960-8","url":null,"abstract":"<p>Liver metastasis remains the primary cause of mortality in patients with colon cancer. Identifying specific driver gene mutations that contribute to metastasis may offer viable therapeutic targets. To explore clonal evolution and genetic heterogeneity within the metastasis, we conducted single-cell exome sequencing on 150 single cells isolated from the primary tumor, liver metastasis, and lymphatic metastasis from a stage IV colon cancer patient. The genetic landscape of the tumor samples revealed that both lymphatic and liver metastases originated from the same region of the primary tumor. Notably, the liver metastasis was derived directly from the primary tumor, bypassing the lymph nodes. Comparative analysis of the sequencing data for individual cell pairs within different tumors demonstrated that the genetic heterogeneity of both liver and lymphatic metastases was also greater than that of the primary tumor. This finding indicates that liver and lymphatic metastases arose from clusters of circulating tumor cell (CTC) of a polyclonal origin, rather than from a single cell from the primary tumor. Single-cell transcriptome analysis suggested that higher EMT score and CNV scores were associated with more polyclonal metastasis. Additionally, a mutation in the <i>TRPS1</i> (Transcriptional repressor GATA binding 1) gene, TRPS1 R544Q, was enriched in the single cells from the liver metastasis. The mutation significantly increased CRC invasion and migration both in vitro and in vivo through the TRPS1^R544Q/ZEB1 axis. Further TRPS1 mutations were detected in additional colon cancer cases, correlating with advanced-stage disease and inferior prognosis. These results reveal polyclonal seeding and <i>TRPS1</i> mutation as potential mechanisms driving the development of liver metastases in colon cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Checkpoint blockade therapy in Hodgkin lymphoma: improved response through combination with JAK inhibition","authors":"Marc A. Weniger, Ralf Küppers","doi":"10.1038/s41392-024-01968-0","DOIUrl":"https://doi.org/10.1038/s41392-024-01968-0","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spliceosomal repression: unleashing human cell totipotency","authors":"Felipe F. Lüttmann, Kee-Pyo Kim, Johnny Kim","doi":"10.1038/s41392-024-01966-2","DOIUrl":"https://doi.org/10.1038/s41392-024-01966-2","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyroptosis in health and disease: mechanisms, regulation and clinical perspective.","authors":"Yifan Liu,Renjie Pan,Yuzhen Ouyang,Wangning Gu,Tengfei Xiao,Hongmin Yang,Ling Tang,Hui Wang,Bo Xiang,Pan Chen","doi":"10.1038/s41392-024-01958-2","DOIUrl":"https://doi.org/10.1038/s41392-024-01958-2","url":null,"abstract":"Pyroptosis is a type of programmed cell death characterized by cell swelling and osmotic lysis, resulting in cytomembrane rupture and release of immunostimulatory components, which play a role in several pathological processes. Significant cellular responses to various stimuli involve the formation of inflammasomes, maturation of inflammatory caspases, and caspase-mediated cleavage of gasdermin. The function of pyroptosis in disease is complex but not a simple angelic or demonic role. While inflammatory diseases such as sepsis are associated with uncontrollable pyroptosis, the potent immune response induced by pyroptosis can be exploited as a therapeutic target for anti-tumor therapy. Thus, a comprehensive review of the role of pyroptosis in disease is crucial for further research and clinical translation from bench to bedside. In this review, we summarize the recent advancements in understanding the role of pyroptosis in disease, covering the related development history, molecular mechanisms including canonical, non-canonical, caspase 3/8, and granzyme-mediated pathways, and its regulatory function in health and multiple diseases. Moreover, this review also provides updates on promising therapeutic strategies by applying novel small molecule inhibitors and traditional medicines to regulate pyroptosis. The present dilemmas and future directions in the landscape of pyroptosis are also discussed from a clinical perspective, providing clues for scientists to develop novel drugs targeting pyroptosis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil extracellular traps in homeostasis and disease.","authors":"Han Wang,Susan J Kim,Yu Lei,Shuhui Wang,Hui Wang,Hai Huang,Hongji Zhang,Allan Tsung","doi":"10.1038/s41392-024-01933-x","DOIUrl":"https://doi.org/10.1038/s41392-024-01933-x","url":null,"abstract":"Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma","authors":"Qiaonan Shan, Lu Yin, Qifan Zhan, Jiongjie Yu, Sheng Pan, Jianyong Zhuo, Wei Zhou, Jiaqi Bao, Lincheng Zhang, Jiachen Hong, Jianan Xiang, Qingyang Que, Kangchen Chen, Shengjun Xu, Jingrui Wang, Yangbo Zhu, Bin He, Jingbang Wu, Haiyang Xie, Shusen Zheng, Tingting Feng, Sunbin Ling, Xiao Xu","doi":"10.1038/s41392-024-01963-5","DOIUrl":"https://doi.org/10.1038/s41392-024-01963-5","url":null,"abstract":"<p>Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irinotecan hydrochloride liposome HR070803 in combination with 5-fluorouracil and leucovorin in locally advanced or metastatic pancreatic ductal adenocarcinoma following prior gemcitabine-based therapy (PAN-HEROIC-1): a phase 3 trial","authors":"Jiujie Cui, Shukui Qin, Yuhong Zhou, Shuang Zhang, Xiaofeng Sun, Mingjun Zhang, Jiuwei Cui, Weijia Fang, Kangsheng Gu, Zhihua Li, Jufeng Wang, Xiaobing Chen, Jun Yao, Jun Zhou, Gang Wang, Yuxian Bai, Juxiang Xiao, Wensheng Qiu, Bangmao Wang, Tao Xia, Chunyue Wang, Li Kong, Jiajun Yin, Tao Zhang, Xionghu Shen, Deliang Fu, Chuntao Gao, Huan Wang, Quanren Wang, Liwei Wang","doi":"10.1038/s41392-024-01948-4","DOIUrl":"https://doi.org/10.1038/s41392-024-01948-4","url":null,"abstract":"<p>Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m² anhydrous irinotecan hydrochloride, equal to 56.5 mg/m² free base) or placebo, both in combination with 5-FU (2000 mg/m²) and LV (200 mg/m²), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1–8.4] versus 5.0 months [95% CI 4.3–6.0]; HR 0.63 [95% CI 0.48–0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}