Signal Transduction and Targeted Therapy最新文献

{"title":"Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas.","authors":"Yan Li, Tongji Xie, Shouzheng Wang, Lin Yang, Xuezhi Hao, Yan Wang, Xingsheng Hu, Lin Wang, Junling Li, Jianming Ying, Puyuan Xing","doi":"10.1038/s41392-024-01981-3","DOIUrl":"10.1038/s41392-024-01981-3","url":null,"abstract":"<p><p>Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type 2 diabetes mellitus in adults: pathogenesis, prevention and therapy.","authors":"Xi Lu, Qingxing Xie, Xiaohui Pan, Ruining Zhang, Xinyi Zhang, Ge Peng, Yuwei Zhang, Sumin Shen, Nanwei Tong","doi":"10.1038/s41392-024-01951-9","DOIUrl":"10.1038/s41392-024-01951-9","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call \"diabetic complications\" as \"MDS-related target organ damage (TOD)\", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of \"MDS-related TOD\".</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":40.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing clinical-basic-clinical research: exploring novel immunotargets for ovarian cancer","authors":"Yuanzhuo Gu, Long Zhang, Weiguo Lv","doi":"10.1038/s41392-024-01970-6","DOIUrl":"https://doi.org/10.1038/s41392-024-01970-6","url":null,"abstract":"&lt;p&gt;In a recent paper published in &lt;i&gt;Cell&lt;/i&gt;,&lt;sup&gt;1&lt;/sup&gt; Luo and colleagues performed a multi-omics analysis of a prospective phase II clinical trial and elucidated the effector regulatory T cells (eTregs) as novel immunotarget for ovarian cancer with homologous recombination deficiency (HRD), analyzing for the first time at the clinical level how poly (ADP-ribose) polymerase (PARP) inhibitors reshape the ovarian cancer microenvironment. The implications of targeting eTregs and combining PARP inhibitors could pave the way for more effective therapies clinically, which is also a typical example of practicing the concept of reverse transformation medicine (RTM) (Fig. 1).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-01970-6/MediaObjects/41392_2024_1970_Fig1_HTML.png?as=webp\" type=\"image/webp\"/&gt;&lt;img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"869\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-024-01970-6/MediaObjects/41392_2024_1970_Fig1_HTML.png\" width=\"685\"/&gt;&lt;/picture&gt;&lt;p&gt;Schematic diagram of the clinical-basic-clinical cycle. The upper panel presents a specific case study exemplifying the integrative clinical-basic-clinical approach, which recently published in a &lt;i&gt;Cell&lt;/i&gt; paper. &lt;b&gt;a&lt;/b&gt; The current therapy for HRD ovarian cancer mainly includes surgery, platinum-based neoadjuvant chemotherapy and PARPi maintenance. On this basis, the authors hope to deeply analyze the unique immune profiles of the ovarian cancer tumor microenvironment and provide clues to the phenomenon that HRD tumors respond to PARPi rather than PD-1 immunotherapy. &lt;b&gt;b&lt;/b&gt; Next, the authors pioneered a clinical trial of neoadjuvant PARPi for oral monotherapy of HRD advanced ovarian cancer (NANT, NCT04507841). &lt;b&gt;c&lt;/b&gt; CCR8&lt;sup&gt;+&lt;/sup&gt; eTregs was then identified as a key responder using multi-modality profiling in clinical samples, emerging as a novel immunotarget for HRD ovarian cancer. &lt;b&gt;d&lt;/b&gt; Anti-CCR8 mAb was successfully verified an effective immunotherapy regimen, which pave the way for the more effective therapies and improving patient outcomes combined with niraparib. &lt;b&gt;e&lt;/b&gt; The lower panel of the diagram illustrates the cyclical loop that connects clinical practice with basic research and back to clinical application, aiming to address key biological questions and to pioneer innovative therapeutic strategies. This process concludes the main four steps: (1) discover new biological insights based on the current clinical therapy; (2) design new clinical trials according to the current unsolved research questions; (3) identify key responders using clinical samples and multi-modality profiling; (4) enlighten novel immunotargets to help develop new clinical therapy&lt;/p&gt;&lt;span&gt;Full size image&lt;/span&gt;&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;us","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329531","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":"Innate immune sensing of danger signals: novel mechanism of heme complex-mediated lytic cell death","authors":"Chintan Chhatbar, Michael Schulz, Roman Sankowski","doi":"10.1038/s41392-024-01985-z","DOIUrl":"https://doi.org/10.1038/s41392-024-01985-z","url":null,"abstract":"<p>In their recent publication in <i>Cell</i>, Sundaram, and colleagues identified a novel role for NOD-like receptor (NLR) family CARD domain containing 5 (NLRC5) in heme-mediated cell death and inflammation.¹ This process is initiated by Toll-like receptors 2 and 4 on the cell surface, which induces intracellular NAD+ depletion and ROS production.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329571","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":"Histone deacetylase inhibition enhances extracellular vesicles from muscle to promote osteogenesis via miR-873-3p","authors":"Ming Chen, Yi Li, Mingming Zhang, Siliang Ge, Taojin Feng, Ruijing Chen, Junmin Shen, Ran Li, Zhongqi Wang, Yong Xie, Duanyang Wang, Jiang Liu, Yuan Lin, Feifan Chang, Junyu Chen, Xinyu Sun, Dongliang Cheng, Xiang Huang, Fanfeng Wu, Qinxiang Zhang, Pingqiang Cai, Pengbin Yin, Licheng Zhang, Peifu Tang","doi":"10.1038/s41392-024-01976-0","DOIUrl":"https://doi.org/10.1038/s41392-024-01976-0","url":null,"abstract":"<p>Regular physical activity is widely recognized for reducing the risk of various disorders, with skeletal muscles playing a key role by releasing biomolecules that benefit multiple organs and tissues. However, many individuals, particularly the elderly and those with clinical conditions, are unable to engage in physical exercise, necessitating alternative strategies to stimulate muscle cells to secrete beneficial biomolecules. Histone acetylation and deacetylation significantly influence exercise-induced gene expression, suggesting that targeting histone deacetylases (HDACs) could mimic some exercise responses. In this study, we explored the effects of the HDAC inhibitor Trichostatin A (TSA) on human skeletal muscle myoblasts (HSMMs). Our findings showed that TSA-induced hyperacetylation enhanced myotube fusion and increased the secretion of extracellular vesicles (EVs) enriched with miR-873-3p. These TSA-EVs promoted osteogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs) by targeting H2 calponin (CNN2). In vivo, systemic administration of TSA-EVs to osteoporosis mice resulted in significant improvements in bone mass. Moreover, TSA-EVs mimicked the osteogenic benefits of exercise-induced EVs, suggesting that HDAC inhibition can replicate exercise-induced bone health benefits. These results demonstrate the potential of TSA-induced muscle-derived EVs as a therapeutic strategy to enhance bone formation and prevent osteoporosis, particularly for individuals unable to exercise. Given the FDA-approved status of various HDAC inhibitors, this approach holds significant promise for rapid clinical translation in osteoporosis treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142329300","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":"Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity","authors":"Cheng Lian, Chunyi Zhang, Pan Tian, Qilong Tan, Yu Wei, Zixian Wang, Qin Zhang, Qixiang Zhang, Mengjie Zhong, Li-Quan Zhou, Xisong Ke, Huabing Zhang, Yao Zhu, Zhenfei Li, Jingdong Cheng, Gong-Hong Wei","doi":"10.1038/s41392-024-01961-7","DOIUrl":"https://doi.org/10.1038/s41392-024-01961-7","url":null,"abstract":"<p>Epigenetic readers frequently affect gene regulation, correlate with disease prognosis, and hold significant potential as therapeutic targets for cancer. Zinc finger MYND-type containing 11 (ZMYND11) is notably recognized for reading the epigenetic marker H3.3K36me3; however, its broader functions and mechanisms of action in cancer remain underexplored. Here, we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients. Depletion of ZMYND11 promotes tumor cell growth, migration, and invasion in vitro, as well as tumor formation and metastasis in vivo. Mechanistically, we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain, thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm. Furthermore, ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio, thus mitigating the aggressive tumor phenotype promoted by PKM2. Remarkably, ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5. Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors. Taken together, our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression, thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328609","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":"Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients: a phase Ib/II trial","authors":"Yaxiong Zhang, Yan Huang, Yunpeng Yang, Yuanyuan Zhao, Ting Zhou, Gang Chen, Shen Zhao, Huaqiang Zhou, Yuxiang Ma, Shaodong Hong, Hongyun Zhao, Li Zhang, Wenfeng Fang","doi":"10.1038/s41392-024-01974-2","DOIUrl":"https://doi.org/10.1038/s41392-024-01974-2","url":null,"abstract":"<p>There is still room for improvement in first-line treatment of advanced small cell lung cancer (SCLC). This trial firstly investigated efficacy and safety of antiangiogenic therapy (surufatinib) (200 mg, qd, po) plus anti-PD-1 treatment (toripalimab) (240 mg, d1, ivdrip) combined with etoposide (100 mg/m², d1-d3, iv, drip) and cisplatin (25 mg/m², d1-d3, ivdrip) for advanced SCLC as first-line treatment, which has been registered on ClinicalTrials.gov under the identifier NCT04996771. The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab. The primary endpoint was progression-free survival (PFS). The secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. All of the 38 patients were enrolled for safety analysis, while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment. After a median follow-up of 21.3 months, the ORR was 97.1% (34/35), and the DCR and the tumor shrinkage rate were both 100% (35/35). The median PFS was 6.9 months (95% CI: 4.6 m–9.2 m) and the median OS was 21.1 months (95% CI: 12.1 m–30.1 m). The 12-month, 18-month, and 24-month OS rates were 66.94%, 51.39% and 38.54%. The occurrence rate of grade ≥3 treatment-emergent adverse events (TEAEs) was 63.2% (24/38), including neutrophil count decreased (31.6%, 12/38), white blood cell count decreased (23.7%, 9/38) and platelet count decreased (10.5%, 4/38). No unexpected adverse events occurred. This novel four-drug regimen (surufatinib, toripalimab, etoposide plus cisplatin) revealed impressive therapeutic efficacy and tolerable toxicities.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321933","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 systemic look at pancreatic cancer patients: Predicting metastasis by studying the liver","authors":"Susanne Roth, Christoph Michalski, Jörg D. Hoheisel","doi":"10.1038/s41392-024-01964-4","DOIUrl":"https://doi.org/10.1038/s41392-024-01964-4","url":null,"abstract":"<p>In a recent paper published in <i>Nature Medicine</i>, Bojmar et al. describe an elaborate effort toward predicting the metastatic progress of pancreatic ductal adenocarcinoma (PDAC) after primary tumour resection.¹ Instead of investigating the tumour, however, they studied several molecular, cellular, and metabolic features in biopsy samples from the seemingly still unaffected liver, which were collected during resection of the primary tumour, demonstrating the large and still neglected biomedical potential of looking at cancer in a systemic manner.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321904","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":"Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system","authors":"Yanli Chang, Jiangli Zhu, Xiaopeng Li, Yi Deng, Birou Lai, Yidan Ma, Jia Tong, Huicong Liu, Juanjuan Li, Chenyu Yang, Qiao Chen, Chengbiao Lu, Yinming Liang, Shiqian Qi, Xiaoning Wang, Eryan Kong","doi":"10.1038/s41392-024-01971-5","DOIUrl":"https://doi.org/10.1038/s41392-024-01971-5","url":null,"abstract":"<p>The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321375","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":"GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia","authors":"Xu Chen, Qingnan Wu, Wei Gong, Shaolong Ju, Jiawen Fan, Xiaohan Gao, Xingyang Liu, Xiao Lei, Siqi Liu, Xiangdong Ming, Qianyu Wang, Ming Fu, Yongmei Song, Yan Wang, Qimin Zhan","doi":"10.1038/s41392-024-01950-w","DOIUrl":"https://doi.org/10.1038/s41392-024-01950-w","url":null,"abstract":"<p>Cachexia, which affects 50–80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75–ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with <i>withanone</i>, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":null,"pages":null},"PeriodicalIF":39.3,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142321316","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}