Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide, characterized by a dismal prognosis and elusive therapeutic targets. Dysregulated cholesterol metabolism is a critical hallmark of cancer cells, facilitating tumor progression. Here, using whole genome sequencing data from several ESCC cohorts, we identified the important role of squalene epoxidase (SQLE) in promoting ESCC tumorigenesis and metastasis. Specifically, our findings highlight the significance of 2,3-oxidosqualene, an intermediate metabolite of cholesterol biosynthesis, synthesized by SQLE and metabolized by lanosterol synthase (LSS), as a key regulator of ESCC progression. Mechanistically, the interaction between 2,3-oxidosqualene and vinculin enhances the nuclear accumulation of Yes-associated protein 1 (YAP), thereby increasing YAP/TEAD-dependent gene expression, and accelerating both tumor growth and metastasis. In a 4-nitroquinoline 1-oxide (4-NQO)-induced ESCC mouse model, overexpression of Sqle resulted in accelerated tumorigenesis compared to wild-type controls, highlighting the pivotal role of SQLE in vivo. Furthermore, elevated SQLE expression in ESCC patients correlates with poorer prognoses, suggesting potential therapeutic avenues for ESCC treatment. In conclusion, our study elucidates the oncogenic function of 2,3-oxidosqualene as a naturally occurring metabolite and proposes modulation of its levels as a promising therapeutic strategy for ESCC.
{"title":"SQLE amplification accelerates esophageal squamous cell carcinoma tumorigenesis and metastasis through oncometabolite 2,3-oxidosqualene repressing Hippo pathway.","authors":"Xuesong Liu, Mengzhu Lv, Bicong Feng, Ying Gong, Qingjie Min, Yan Wang, Qingnan Wu, Jie Chen, Dongyu Zhao, Jinting Li, Weimin Zhang, Qimin Zhan","doi":"10.1016/j.canlet.2025.217528","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217528","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent cancers worldwide, characterized by a dismal prognosis and elusive therapeutic targets. Dysregulated cholesterol metabolism is a critical hallmark of cancer cells, facilitating tumor progression. Here, using whole genome sequencing data from several ESCC cohorts, we identified the important role of squalene epoxidase (SQLE) in promoting ESCC tumorigenesis and metastasis. Specifically, our findings highlight the significance of 2,3-oxidosqualene, an intermediate metabolite of cholesterol biosynthesis, synthesized by SQLE and metabolized by lanosterol synthase (LSS), as a key regulator of ESCC progression. Mechanistically, the interaction between 2,3-oxidosqualene and vinculin enhances the nuclear accumulation of Yes-associated protein 1 (YAP), thereby increasing YAP/TEAD-dependent gene expression, and accelerating both tumor growth and metastasis. In a 4-nitroquinoline 1-oxide (4-NQO)-induced ESCC mouse model, overexpression of Sqle resulted in accelerated tumorigenesis compared to wild-type controls, highlighting the pivotal role of SQLE in vivo. Furthermore, elevated SQLE expression in ESCC patients correlates with poorer prognoses, suggesting potential therapeutic avenues for ESCC treatment. In conclusion, our study elucidates the oncogenic function of 2,3-oxidosqualene as a naturally occurring metabolite and proposes modulation of its levels as a promising therapeutic strategy for ESCC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217528"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381685","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}
Pub Date : 2025-02-07DOI: 10.1016/j.canlet.2025.217522
Sugarniya Subramaniam, Varinder Jeet, Jennifer H Gunter, Judith A Clements, Srilakshmi Srinivasan, Amirali Popat, Jyotsna Batra
Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.
{"title":"Lactoferrin-Encapsulated Dichloroacetophenone (DAP) nanoparticles enhance drug delivery and anti-tumor efficacy in prostate cancer.","authors":"Sugarniya Subramaniam, Varinder Jeet, Jennifer H Gunter, Judith A Clements, Srilakshmi Srinivasan, Amirali Popat, Jyotsna Batra","doi":"10.1016/j.canlet.2025.217522","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217522","url":null,"abstract":"<p><p>Pyruvate Dehydrogenase Kinase 1 (PDK1) regulates glycolysis and oxidative phosphorylation pathways and is linked to prostate cancer metastasis and poor prognosis. The therapeutic application of 2,2-dichloroacetophenone (DAP), a PDK1 inhibitor, remains underexplored in prostate cancer. In this study we demonstrated that DAP exhibited a superior ability to inhibit prostate cancer cell proliferation, migration and colony formation at a lower concentration (20 μM) compared to a previously established inhibitor, dichloroacetate (DCA), which required concentrations of 30 mM or higher. However, poor aqueous solubility and lower stability of DAP limits its therapeutic application. Nano formulation of DAP with natural lactoferrin enhanced its dispersion and stability by increasing polydispersity index and intensity, and reduced zeta potential values upon conjugation that overcame the solubility limitations of DAP. The lactoferrin-DAP nanoparticles exhibited enhanced therapeutic efficacy by precisely targeting prostate cancer cells that express high lactoferrin receptors and high anti-tumor activity in vitro (at 1 μM) and in mouse prostate tumor xenografts (20 mg/kg). Mechanistically, these nanoparticles induce apoptosis in cancer cells by inducing caspase3/7 activity and disrupting the glycolytic and oxidative phosphorylation pathways. Moreover, lactoferrin-conjugated DAP nanoparticles suppressed the viability of docetaxel-resistant cells exhibiting a higher inhibitory efficacy compared to free DAP and DCA. Targeting PDK1 through lactoferrin-conjugated DAP nanoparticles represents a potent targeted therapeutic strategy for disrupting prostate tumor metabolism and offers promising implications for overcoming drug resistance.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217522"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381515","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}
Pub Date : 2025-02-07DOI: 10.1016/j.canlet.2025.217537
Riccardo Ballarò , Amanda R. Wasylishen , Carolina R.C. Pieterman , Courtney Olsen , Ehsan Irajizad , Ranran Wu , Hiroyuki Katayama , Huiling Liu , Yining Cai , Ricardo A. León-Letelier , Jennifer B. Dennison , Steven Waguespack , Kim-Anh Do , Sunita K. Agarwal , Mary Walter , James Welch , Lee Weinstein , Jenny E. Blau , Smita Jha , Naris Nilubol , Johannes F. Fahrmann
Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to Fusobacterium nucleatum, Faecalibacterium prausnitzii, and Klebsiella pneumoniae and negatively correlated with Streptococcus pneumoniae and Streptococcus thermophilus. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85–1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an Men1fl/flPdx1-CreTg mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.
{"title":"Elevated levels of circulating microbial-associated uremic toxins are associated with metastatic duodenopancreatic neuroendocrine tumors in patients with Multiple Endocrine Neoplasia Type 1","authors":"Riccardo Ballarò , Amanda R. Wasylishen , Carolina R.C. Pieterman , Courtney Olsen , Ehsan Irajizad , Ranran Wu , Hiroyuki Katayama , Huiling Liu , Yining Cai , Ricardo A. León-Letelier , Jennifer B. Dennison , Steven Waguespack , Kim-Anh Do , Sunita K. Agarwal , Mary Walter , James Welch , Lee Weinstein , Jenny E. Blau , Smita Jha , Naris Nilubol , Johannes F. Fahrmann","doi":"10.1016/j.canlet.2025.217537","DOIUrl":"10.1016/j.canlet.2025.217537","url":null,"abstract":"<div><div>Metastatic duodenopancreatic neuroendocrine tumors (dpNETs) are the primary cause of mortality among patients with Multiple Endocrine Neoplasia Type 1 (MEN1). Emerging evidence implicates the microbiome and microbial-derived secreted factors in promoting cancer development and progression. In the current study, we report that the circulating microbial-associated uremic toxins trimethylamine N-oxide (TMAO), indoxyl sulfate (IS), cresol sulfate (CS), cresol glucuronide (CG), and phenol sulfate (PS) are elevated in MEN1 patients with metastatic dpNETs. Proteomic- and metabolomic-based analysis of resected dpNET tissues from MEN1 patients also revealed detectable levels of uremic toxins that positively correlated with peptide-based signatures corresponding to <em>Fusobacterium nucleatum</em>, <em>Faecalibacterium prausnitzii,</em> and <em>Klebsiella pneumoniae</em> and negatively correlated with <em>Streptococcus pneumoniae</em> and <em>Streptococcus thermophilus</em>. A microbial-associated uremic toxin panel (MUTP) was developed and, in an independent case-control validation cohort, the panel yielded an area under the receiver operating characteristic curve (AUC) of 0.94 (95 % CI: 0.85–1.00) with 67 % sensitivity at 95 % specificity for identifying MEN1 patients with metastatic dpNETS. Increases in circulating microbial-associated uremic toxins during early stages of neoplasia were also found to be associated with poor overall survival in an <em>Men1</em><sup><em>fl/fl</em></sup><em>Pdx1-Cre</em><sup><em>Tg</em></sup> mouse model of MEN1 pancreatic NETs. Our findings suggest that microbial dysbiosis is associated with disease aggressiveness and that increases in circulating microbial-associated uremic toxins may be a prognostic indication for MEN1 individuals who are at risk of having metastatic dpNETs.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217537"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381502","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}
Pub Date : 2025-02-07DOI: 10.1016/j.canlet.2025.217536
Sara Lorenzoni , Carlos Rodríguez-Nogales , María J. Blanco-Prieto
The need for precision therapies arises from the complexities associated with high-risk types of cancer, due to their aggressiveness and resistance to treatment. These diseases represent a global issue that requires transversal strategies involving cooperation among oncology specialists and experts from related fields, including nanomedicine. Nanoparticle-mediated active targeting of tumors has proven to be a revolutionary approach to address the most challenging neoplasms by overcoming the poor permeation at tumor site of untargeted, and nowadays questioned, strategies that rely solely on Enhanced Permeability and Retention (EPR) effects. The decoration of nanoparticles with Arg-Gly-Asp (RGD) peptides, which selectively target integrins on the cell membrane, marks a turning point in tumor microenvironment (TME) targeted strategies, enabling precision and efficiency in the delivery of chemotherapeutics. This review delves into the intricacies of the TME's features and targetable components (i.e. integrins), and the development of RGDs for nanoparticles' functionalization for active TME targeting. It provides a translational perspective on the integration of RGD-functionalized nanoparticles in oncology, highlighting their potential to overcome current therapeutic challenges, particularly in precision medicine. The current landscape of targeted nanomedicines in the clinic, and the development of RGD-nanomedicine for pediatric cancers are also discussed.
{"title":"Targeting tumor microenvironment with RGD-functionalized nanoparticles for precision cancer therapy","authors":"Sara Lorenzoni , Carlos Rodríguez-Nogales , María J. Blanco-Prieto","doi":"10.1016/j.canlet.2025.217536","DOIUrl":"10.1016/j.canlet.2025.217536","url":null,"abstract":"<div><div>The need for precision therapies arises from the complexities associated with high-risk types of cancer, due to their aggressiveness and resistance to treatment. These diseases represent a global issue that requires transversal strategies involving cooperation among oncology specialists and experts from related fields, including nanomedicine. Nanoparticle-mediated active targeting of tumors has proven to be a revolutionary approach to address the most challenging neoplasms by overcoming the poor permeation at tumor site of untargeted, and nowadays questioned, strategies that rely solely on Enhanced Permeability and Retention (EPR) effects. The decoration of nanoparticles with Arg-Gly-Asp (RGD) peptides, which selectively target integrins on the cell membrane, marks a turning point in tumor microenvironment (TME) targeted strategies, enabling precision and efficiency in the delivery of chemotherapeutics. This review delves into the intricacies of the TME's features and targetable components (<em>i.e.</em> integrins), and the development of RGDs for nanoparticles' functionalization for active TME targeting. It provides a translational perspective on the integration of RGD-functionalized nanoparticles in oncology, highlighting their potential to overcome current therapeutic challenges, particularly in precision medicine. The current landscape of targeted nanomedicines in the clinic, and the development of RGD-nanomedicine for pediatric cancers are also discussed.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217536"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381686","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}
Pub Date : 2025-02-07DOI: 10.1016/j.canlet.2025.217542
Ya-Hui Li, Xiao-Jun Huang, Xiang-Yu Zhao
Immune synapses, which were initially discovered at the interface between antigen-presenting cells (APCs) and T cells, are special structures formed at the contact site between antigen-presenting cells and immune cells and constitute the structural basis for immune cells to kill tumours and synthesise antibodies. Their structures are very similar to those of neural synapses in the nervous system, and they contain different functional structural regions.
With the development of cell visualization research, scientists have increasingly conducted in-depth research on immune synapses. At present, it is known that T cells, B cells, and NK cells can form different immune synapses with target cells. Immune synapses formed by different cell subsets as well as CAR-T cells have their own characteristics, mainly in terms of their structure, formation process and regulatory mechanism. Therefore, how to enhance immune cell killing function by enhancing immune synaptic function has long been a research hotspot. At present, the killing function of immune cells can be enhanced by influencing the signalling molecules of immune synapses and the cell microenvironment and modifying the structure of immune synapses. Through a review of the factors affecting immune synapses, we can better explore the target for enhancing immune system function.
免疫突触最初是在抗原递呈细胞（APC）和 T 细胞之间的界面上发现的，是抗原递呈细胞和免疫细胞接触部位形成的特殊结构，是免疫细胞杀死肿瘤和合成抗体的结构基础。它们的结构与神经系统中的神经突触非常相似，包含不同的功能结构区域。随着细胞可视化研究的发展，科学家们对免疫突触的研究越来越深入。目前已知，T 细胞、B 细胞和 NK 细胞可以与靶细胞形成不同的免疫突触。不同细胞亚群以及 CAR-T 细胞形成的免疫突触各有特点，主要体现在其结构、形成过程和调控机制等方面。因此，如何通过增强免疫突触功能来提高免疫细胞的杀伤功能一直是研究热点。目前，可以通过影响免疫突触的信号分子和细胞微环境以及改变免疫突触的结构来增强免疫细胞的杀伤功能。通过回顾影响免疫突触的因素，我们可以更好地探索增强免疫系统功能的目标。
{"title":"Translational study of the regulatory mechanism by which immune synapses enhance immune cell function","authors":"Ya-Hui Li, Xiao-Jun Huang, Xiang-Yu Zhao","doi":"10.1016/j.canlet.2025.217542","DOIUrl":"10.1016/j.canlet.2025.217542","url":null,"abstract":"<div><div>Immune synapses, which were initially discovered at the interface between antigen-presenting cells (APCs) and T cells, are special structures formed at the contact site between antigen-presenting cells and immune cells and constitute the structural basis for immune cells to kill tumours and synthesise antibodies. Their structures are very similar to those of neural synapses in the nervous system, and they contain different functional structural regions.</div><div>With the development of cell visualization research, scientists have increasingly conducted in-depth research on immune synapses. At present, it is known that T cells, B cells, and NK cells can form different immune synapses with target cells. Immune synapses formed by different cell subsets as well as CAR-T cells have their own characteristics, mainly in terms of their structure, formation process and regulatory mechanism. Therefore, how to enhance immune cell killing function by enhancing immune synaptic function has long been a research hotspot. At present, the killing function of immune cells can be enhanced by influencing the signalling molecules of immune synapses and the cell microenvironment and modifying the structure of immune synapses. Through a review of the factors affecting immune synapses, we can better explore the target for enhancing immune system function.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217542"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381687","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}
Pub Date : 2025-02-07DOI: 10.1016/j.canlet.2025.217535
Aiwen Jian, Guo Zhao, Jiawei Zhou, Shuhang Wang, Ning Li
{"title":"How to Design Next-generation of Antibody-Drug Conjugates for Cancer Treatment: Lessons from Unsuccessful Clinical Trials.","authors":"Aiwen Jian, Guo Zhao, Jiawei Zhou, Shuhang Wang, Ning Li","doi":"10.1016/j.canlet.2025.217535","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217535","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217535"},"PeriodicalIF":9.1,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381503","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}
Pub Date : 2025-02-06DOI: 10.1016/j.canlet.2025.217523
Yumeng Hu , Yifu Hu , Shaobo Zhang , Yuanyuan Guo , Fangxia Wang , Yongxing Du , Lijuan Wang , Pengxue Li , Yan Xu , Hui Zhang , Zhikai Yang , Zhihua Liu , Jingyong Xu , Mingyang Liu
Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through in vivo experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.
{"title":"Tumor-derived miR-203a-3p potentiates muscle wasting by inducing muscle ferroptosis in pancreatic cancer","authors":"Yumeng Hu , Yifu Hu , Shaobo Zhang , Yuanyuan Guo , Fangxia Wang , Yongxing Du , Lijuan Wang , Pengxue Li , Yan Xu , Hui Zhang , Zhikai Yang , Zhihua Liu , Jingyong Xu , Mingyang Liu","doi":"10.1016/j.canlet.2025.217523","DOIUrl":"10.1016/j.canlet.2025.217523","url":null,"abstract":"<div><div>Pancreatic cancer (PC) cachexia, characterized by profound muscle wasting and systemic inflammation, remains a formidable clinical challenge due to its multifactorial nature and complex molecular underpinnings. This study delves into the intricate interplay between microRNA (miRNA) dysregulation and ferroptosis, a form of iron-dependent cell death, in PC cachexia. Specifically, we identified tumor-derived miR-203a-3p as a pivotal miRNA that promotes muscle atrophy by upregulating muscle ferroptosis. Our findings revealed that miR-203a-3p targets zinc finger E-box binding homeobox 1 (ZEB1), subsequently enhancing the expression of the iron transporter solute carrier family 11 member 2 (SLC11A2), thereby facilitating ferroptosis-associated skeletal muscle cell death. Through <em>in vivo</em> experiments using a PC cachexic mouse model, we demonstrated that inhibiting ferroptosis effectively attenuated muscle wasting, highlighting its critical role in the pathogenesis of PC cachexia. These results provide a molecular framework elucidating how miRNA regulation and ferroptosis converge to drive muscle atrophy, offering novel therapeutic avenues for mitigating cachexia in PC patients. By targeting these pathways, we aim to improve muscle preservation and overall survival in this devastating disease.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217523"},"PeriodicalIF":9.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373847","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}
Pub Date : 2025-02-06DOI: 10.1016/j.canlet.2025.217510
Yuning Wang , Shuhang Wang, Ning Li
{"title":"Accelerating the clinical translation of CD70-targeted chimeric antigen receptor-based cell therapies in oncology: A comprehensive clinical investigation panorama analysis based on the Trialtrove database","authors":"Yuning Wang , Shuhang Wang, Ning Li","doi":"10.1016/j.canlet.2025.217510","DOIUrl":"10.1016/j.canlet.2025.217510","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217510"},"PeriodicalIF":9.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373846","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}
Pub Date : 2025-02-04DOI: 10.1016/j.canlet.2025.217509
Xiangpan Li , Jiatong Lu , Fangfang Chen , Jingwen Yuan , Yunfei Zha , Ying Li , Junfeng Yan , Qiang Li , Jingping Yuan , Qiang Tong
Peritoneal metastasis following gastric cancer surgery is often associated with a poor prognosis. This study aimed to investigate the mechanisms underlying peritoneal metastasis and to develop a predictive model for the risk of postoperative peritoneal metastases in gastric cancer. We performed a comprehensive analysis of the protein mass spectra and tumor microenvironment in paraffin-embedded primary tumor sections from gastric cancer patients, both with and without postoperative peritoneal metastases. Using proteomic profiling, we identified 9595 proteins and stratified patients into three distinct proteomic subgroups (Pro1, Pro2, Pro3) based on differential protein expression. Simultaneously, immune cell profiling allowed us to classify patients into four immune subgroups (IG-I, IG-II, IG-III, IG-IV). The relationships between these proteomic, immune, and metastasis classifications were further explored to uncover potential associations and mechanisms driving metastasis. Building on these insights, we developed an integrative model combining proteomics, immunological, and radiomics data for predicting postoperative peritoneal metastases. This model demonstrated high predictive efficacy, offering a robust tool for identifying high-risk patients. Our findings provide a deeper understanding of the biological processes underlying peritoneal metastasis in gastric cancer, highlighting the interplay between proteomic and immune factors. By establishing novel patient subgroups and an effective prediction model, this study lays the groundwork for early diagnosis and tailored therapeutic strategies to improve outcomes for gastric cancer patients.
{"title":"Comprehensive proteomic analysis and multidimensional model construction of peritoneal metastasis in gastric cancer","authors":"Xiangpan Li , Jiatong Lu , Fangfang Chen , Jingwen Yuan , Yunfei Zha , Ying Li , Junfeng Yan , Qiang Li , Jingping Yuan , Qiang Tong","doi":"10.1016/j.canlet.2025.217509","DOIUrl":"10.1016/j.canlet.2025.217509","url":null,"abstract":"<div><div>Peritoneal metastasis following gastric cancer surgery is often associated with a poor prognosis. This study aimed to investigate the mechanisms underlying peritoneal metastasis and to develop a predictive model for the risk of postoperative peritoneal metastases in gastric cancer. We performed a comprehensive analysis of the protein mass spectra and tumor microenvironment in paraffin-embedded primary tumor sections from gastric cancer patients, both with and without postoperative peritoneal metastases. Using proteomic profiling, we identified 9595 proteins and stratified patients into three distinct proteomic subgroups (Pro1, Pro2, Pro3) based on differential protein expression. Simultaneously, immune cell profiling allowed us to classify patients into four immune subgroups (IG-I, IG-II, IG-III, IG-IV). The relationships between these proteomic, immune, and metastasis classifications were further explored to uncover potential associations and mechanisms driving metastasis. Building on these insights, we developed an integrative model combining proteomics, immunological, and radiomics data for predicting postoperative peritoneal metastases. This model demonstrated high predictive efficacy, offering a robust tool for identifying high-risk patients. Our findings provide a deeper understanding of the biological processes underlying peritoneal metastasis in gastric cancer, highlighting the interplay between proteomic and immune factors. By establishing novel patient subgroups and an effective prediction model, this study lays the groundwork for early diagnosis and tailored therapeutic strategies to improve outcomes for gastric cancer patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"614 ","pages":"Article 217509"},"PeriodicalIF":9.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363658","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}
Pub Date : 2025-02-04DOI: 10.1016/j.canlet.2025.217531
Ornella Urzì , Roger Olofsson Bagge , Rossella Crescitelli
Uveal melanoma (UM), which originates from the uveal tract of the eye, is the most common and aggressive intraocular cancer in adults. The detection of genetic markers is crucial for an accurate diagnosis, but this requires tumor biopsies that can be challenging to obtain. Extracellular vesicles (EVs) have emerged as potential biomarkers for UM due to their presence in biological fluids and their ability to carry disease-related biomolecules such as proteins and nucleic acids. Increasing evidence indicates that EVs released from UM cells play crucial roles in UM development, including cancer progression, pre-metastatic niche formation, and metastasis. Moreover, many studies have demonstrated that UM-derived EVs carry proteins and microRNAs that might be used as biomarkers. This review explores the role of EVs in UM, focusing on their biological functions and their potential as diagnostic and prognostic biomarkers of UM. Additionally, current challenges to the use of UM-derived EVs in clinical translation were identified, as well as perspectives and future directions in the field.
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