Pub Date : 2026-04-01Epub Date: 2026-02-21DOI: 10.1016/j.neo.2026.101291
Jie Chen , Xinyu Chu , Yue Wu , Li Su , Mingqi Wang , Xuemei Zhao , Xiaohong Wei , Guiyang Xia , Huan Xia , Sheng Lin , Mei Zhang
Chemotherapy-related cognitive impairment (CRCI), colloquially termed “chemobrain,” remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.
{"title":"Mechanistic insights and therapeutic interventions of mitochondrial quality control in chemotherapy-related cognitive impairment","authors":"Jie Chen , Xinyu Chu , Yue Wu , Li Su , Mingqi Wang , Xuemei Zhao , Xiaohong Wei , Guiyang Xia , Huan Xia , Sheng Lin , Mei Zhang","doi":"10.1016/j.neo.2026.101291","DOIUrl":"10.1016/j.neo.2026.101291","url":null,"abstract":"<div><div>Chemotherapy-related cognitive impairment (CRCI), colloquially termed “chemobrain,” remains a debilitating and underaddressed sequela of cancer treatment. Despite its prevalence and profound impact on quality of life, the precise pathophysiological mechanisms remain incompletely understood. This review synthesizes emerging evidence positioning mitochondrial quality control (MQC) dysfunction as a central mechanistic hub in CRCI pathogenesis. We critically evaluate how diverse chemotherapeutic agents, including anthracyclines, alkylating agents, platinum compounds, antimetabolites, and microtubule inhibitors, converge on distinct yet overlapping pathways of MQC impairment. These agent-specific mechanisms collectively compromise the five fundamental pillars of MQC: biogenesis, mitophagy, dynamics, and proteostasis, along with the formation of mitochondria-derived vesicles. MQC failure subsequently drives a feed-forward cycle of neuroinflammation, blood-brain barrier disruption, synaptic loss, and ultimately, cognitive dysfunction. We further examine promising therapeutic strategies targeting MQC, encompassing mitochondria-targeted antioxidants, metabolic regulators, biogenesis activators, mitochondrial dynamics modulators, mitophagy activators, multi-targeted drugs, as well as physical and nutritional interventions that collectively enhance neuronal mitochondrial resilience. By elucidating the mechanistic centrality of MQC in CRCI, this review provides a robust framework for developing targeted interventions that may preserve cognitive function without compromising anticancer efficacy, thereby addressing a critical unmet need in cancer survivorship care and accelerating the transition towards precision neuroprotection in oncology.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"74 ","pages":"Article 101291"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-04-01Epub Date: 2026-02-26DOI: 10.1016/j.neo.2026.101290
Shiwang Wu , Xinyi Ye , Jingsi Wang , Mei Li , Yage Fu , Shan Wang
The oral-gut microbiota axis is increasingly recognized as a critical bridge linking local infection to systemic diseases. Growing evidence demonstrates that oral microbes not only enter the gut via saliva, bloodstream, and direct migration but also successfully colonize under specific microenvironmental conditions, reshaping the local microbial ecosystem. Periodontal pathogens such as P. gingivalis and F. nucleatum drive gastrointestinal tumorigenesis through chronic inflammation, metabolite production, and signaling pathway reprogramming. Moreover, oral–gut microbial interactions reveal cancer-specific risk patterns, with distinct roles in esophageal, gastric, colorectal, and pancreatic cancers. This review not only highlights the key mechanisms by which oral microbes promote tumor development but also emphasizes their clinical potential as diagnostic biomarkers and therapeutic targets, offering novel directions for translational research on the oral-gut axis.
{"title":"Microbial crosstalk along the oral–gut axis: organ-specific oncogenic adaptations of Porphyromonas gingivalis and Fusobacterium nucleatum","authors":"Shiwang Wu , Xinyi Ye , Jingsi Wang , Mei Li , Yage Fu , Shan Wang","doi":"10.1016/j.neo.2026.101290","DOIUrl":"10.1016/j.neo.2026.101290","url":null,"abstract":"<div><div>The oral-gut microbiota axis is increasingly recognized as a critical bridge linking local infection to systemic diseases. Growing evidence demonstrates that oral microbes not only enter the gut via saliva, bloodstream, and direct migration but also successfully colonize under specific microenvironmental conditions, reshaping the local microbial ecosystem. Periodontal pathogens such as <em>P. gingivalis</em> and <em>F. nucleatum</em> drive gastrointestinal tumorigenesis through chronic inflammation, metabolite production, and signaling pathway reprogramming. Moreover, oral–gut microbial interactions reveal cancer-specific risk patterns, with distinct roles in esophageal, gastric, colorectal, and pancreatic cancers. This review not only highlights the key mechanisms by which oral microbes promote tumor development but also emphasizes their clinical potential as diagnostic biomarkers and therapeutic targets, offering novel directions for translational research on the oral-gut axis.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"74 ","pages":"Article 101290"},"PeriodicalIF":7.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-20DOI: 10.1016/j.neo.2026.101292
Teresa Schmid , Julia Maier , Melanie Martin , Alpaslan Tasdogan , Eugen Tausch , Thomas F.E. Barth , Stephan Stilgenbauer , Johannes Bloehdorn , Peter Möller , Kevin Mellert
{"title":"Corrigendum to “U-RT1 – A new model for Richter transformation” [Neoplasia Volume 23, Issue 1, January 2021, Pages 140-148]","authors":"Teresa Schmid , Julia Maier , Melanie Martin , Alpaslan Tasdogan , Eugen Tausch , Thomas F.E. Barth , Stephan Stilgenbauer , Johannes Bloehdorn , Peter Möller , Kevin Mellert","doi":"10.1016/j.neo.2026.101292","DOIUrl":"10.1016/j.neo.2026.101292","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101292"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-31DOI: 10.1016/j.neo.2026.101277
Keran Sun , Jingyuan Ning , Keqi Jia , Xiaoqing Fan , Hongru Li , Cuiqing Ma , Lin Wei
Background
Chemokine receptor 1 (CCR1), a regulator of immune cell migration, has been implicated in various cancers but remains poorly characterized in gastric cancer's immune microenvironment. This study aimed to investigate whether CCR1 promotes or suppresses tumor progression in gastric cancer.
Methods
Utilize transcriptomic analysis to investigate the role of CCR1 in gastric cancer, and employed clinical data to examine the correlation between CCR1 expression and patient survival as well as pathological features. In vivo models with CCR1-knockout mice and macrophage depletion experiments validated functional roles, while Western blotting and qRT-PCR explored The pathways and signaling.
Results
Following patient stratification based on optimal cut-off values, Kaplan-Meier survival analysis demonstrated that patients with high CCR1 expression had longer survival times. Single-cell and spatial transcriptomics analyses revealed that CCR1 is predominantly expressed on macrophages. Immunofluorescence assays showed greater co-localization of CCR1 and CD68 in gastric cancer tissues compared to adjacent normal tissues, confirming CCR1 expression in macrophages. In vivo experiments demonstrated that CCR1 deficiency increased tumor growth by reducing T cell infiltration, an effect that was abrogated by macrophage depletion. Mechanistically, CCR1 activates the NF-κB and MAPK pathways in macrophages to upregulate CXCL9 and CXCL10, thereby promoting T cell recruitment to the tumor microenvironment.
Conclusions
CCR1 modulates T cell distribution via CXCL9/CXCL10, suggesting potential therapeutic directions.
{"title":"The Role of CCR1 as a decisive factor for immune response activation versus suppression phenotypes in gastric cancer","authors":"Keran Sun , Jingyuan Ning , Keqi Jia , Xiaoqing Fan , Hongru Li , Cuiqing Ma , Lin Wei","doi":"10.1016/j.neo.2026.101277","DOIUrl":"10.1016/j.neo.2026.101277","url":null,"abstract":"<div><h3>Background</h3><div>Chemokine receptor 1 (CCR1), a regulator of immune cell migration, has been implicated in various cancers but remains poorly characterized in gastric cancer's immune microenvironment. This study aimed to investigate whether CCR1 promotes or suppresses tumor progression in gastric cancer.</div></div><div><h3>Methods</h3><div>Utilize transcriptomic analysis to investigate the role of CCR1 in gastric cancer, and employed clinical data to examine the correlation between CCR1 expression and patient survival as well as pathological features. In vivo models with CCR1-knockout mice and macrophage depletion experiments validated functional roles, while Western blotting and qRT-PCR explored The pathways and signaling.</div></div><div><h3>Results</h3><div>Following patient stratification based on optimal cut-off values, Kaplan-Meier survival analysis demonstrated that patients with high CCR1 expression had longer survival times. Single-cell and spatial transcriptomics analyses revealed that CCR1 is predominantly expressed on macrophages. Immunofluorescence assays showed greater co-localization of CCR1 and CD68 in gastric cancer tissues compared to adjacent normal tissues, confirming CCR1 expression in macrophages. In vivo experiments demonstrated that CCR1 deficiency increased tumor growth by reducing T cell infiltration, an effect that was abrogated by macrophage depletion. Mechanistically, CCR1 activates the NF-κB and MAPK pathways in macrophages to upregulate CXCL9 and CXCL10, thereby promoting T cell recruitment to the tumor microenvironment.</div></div><div><h3>Conclusions</h3><div>CCR1 modulates T cell distribution via CXCL9/CXCL10, suggesting potential therapeutic directions.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101277"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146100990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-14DOI: 10.1016/j.neo.2026.101288
Fan Yang , Lin Chen , Yuchen Shi , Lude Wang , Minfeng Tong
Introduction
SMARCA4, a pivotal transcription activator regulating chromatin structure, gene expression, and cellular energy metabolism, has well-documented roles in various cancers. However, its specific function in glioblastoma (GBM) pathogenesis remains underexplored. This study investigates the correlation between SMARCA4 expression and GBM progression, with a focus on the tumor microenvironment.
Materials and methods
Single-cell RNA sequencing analyzed dynamic niche cell proportion shifts (e.g., mesenchymal stromal cells, MSCs) during GBM progression. SMARCA4 knockdown was executed in MSCs for in vitro functional evaluations, while an immunodeficient xenograft model was utilized to assess the impact of SMARCA4-deficient MSCs on in vivo GBM progression. Mechanistic studies focused on microtubule-dependent mitochondrial transfer in IDH mutant/wild-type tumors.
Results
SMARCA4 was identified as a critical MSC regulator. Its knockdown altered MSC/GBM cell behavior in vitro, accelerated in vivo GBM progression, and worsened outcomes. SMARCA4-deficient MSCs enhanced GBM growth via mitochondrial transfer, altering MSC proliferative phenotype but increasing mitochondrial metabolic capacity.
Discussion
Our findings highlight SMARCA4’s critical role in regulating MSC function within the GBM microenvironment. Targeting SMARCA4-mediated mitochondrial transfer in MSCs may represent a novel therapeutic strategy for GBM.
{"title":"SMARCA4 deficiency in glioblastoma: Mitochondrial transfer from MSCs and the clinical dilemma in targeting the tumor microenvironment","authors":"Fan Yang , Lin Chen , Yuchen Shi , Lude Wang , Minfeng Tong","doi":"10.1016/j.neo.2026.101288","DOIUrl":"10.1016/j.neo.2026.101288","url":null,"abstract":"<div><h3>Introduction</h3><div>SMARCA4, a pivotal transcription activator regulating chromatin structure, gene expression, and cellular energy metabolism, has well-documented roles in various cancers. However, its specific function in glioblastoma (GBM) pathogenesis remains underexplored. This study investigates the correlation between SMARCA4 expression and GBM progression, with a focus on the tumor microenvironment.</div></div><div><h3>Materials and methods</h3><div>Single-cell RNA sequencing analyzed dynamic niche cell proportion shifts (e.g., mesenchymal stromal cells, MSCs) during GBM progression. SMARCA4 knockdown was executed in MSCs for in vitro functional evaluations, while an immunodeficient xenograft model was utilized to assess the impact of SMARCA4-deficient MSCs on in vivo GBM progression. Mechanistic studies focused on microtubule-dependent mitochondrial transfer in IDH mutant/wild-type tumors.</div></div><div><h3>Results</h3><div>SMARCA4 was identified as a critical MSC regulator. Its knockdown altered MSC/GBM cell behavior in vitro, accelerated in vivo GBM progression, and worsened outcomes. SMARCA4-deficient MSCs enhanced GBM growth via mitochondrial transfer, altering MSC proliferative phenotype but increasing mitochondrial metabolic capacity.</div></div><div><h3>Discussion</h3><div>Our findings highlight SMARCA4’s critical role in regulating MSC function within the GBM microenvironment. Targeting SMARCA4-mediated mitochondrial transfer in MSCs may represent a novel therapeutic strategy for GBM.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101288"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146203446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-28DOI: 10.1016/j.neo.2026.101275
Shams Al-Azzam , Isabella Stuewe , Sunandini Sharma , Miki Yamada-Hara , Arisachi Tanaka , Kegan Stringer , Merna Behnam , Norah Al-Azzam , Shuvro Nandi , Maria Zhivagui , Janelle Duong , Ting Yang , Scott Herdman , Maripat Corr , Nicholas J. G Webster , Eyal Raz , Ludmil B Alexandrov , Samuel Bertin
Chronic exposure to the common aeroallergen house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung cancer development remains largely unexplored. Using whole-genome sequencing, RNA-seq, and DNA methylation profiling, we assessed HDM effects in lung epithelial cell lines and a mouse orthotopic lung cancer model. HDM accelerated tumor growth without altering mutational burden. Transcriptomic and epigenetic analyses revealed tissue-specific effects: in normal lung, HDM enhanced pro-inflammatory and immune activation programs, whereas in tumors it suppressed T cell responses, antigen presentation, and chemokine signaling. Immune deconvolution showed a shift toward myeloid enrichment and lymphoid suppression, with reduced cytotoxic T and NK signatures. Notably, HDM-driven tumor promotion was abolished in Il17a−/− but not Il1b−/− mice, identifying IL-17A as a critical mediator. These findings demonstrate that chronic aeroallergen exposure reshapes the lung microenvironment to promote immune suppression and accelerate lung cancer progression.
{"title":"Multi-omics profiling reveals microenvironmental remodeling as a key driver of house dust mite-induced lung cancer progression","authors":"Shams Al-Azzam , Isabella Stuewe , Sunandini Sharma , Miki Yamada-Hara , Arisachi Tanaka , Kegan Stringer , Merna Behnam , Norah Al-Azzam , Shuvro Nandi , Maria Zhivagui , Janelle Duong , Ting Yang , Scott Herdman , Maripat Corr , Nicholas J. G Webster , Eyal Raz , Ludmil B Alexandrov , Samuel Bertin","doi":"10.1016/j.neo.2026.101275","DOIUrl":"10.1016/j.neo.2026.101275","url":null,"abstract":"<div><div>Chronic exposure to the common aeroallergen house dust mite (HDM) induces lung inflammation and DNA damage, but its impact on lung cancer development remains largely unexplored. Using whole-genome sequencing, RNA-seq, and DNA methylation profiling, we assessed HDM effects in lung epithelial cell lines and a mouse orthotopic lung cancer model. HDM accelerated tumor growth without altering mutational burden. Transcriptomic and epigenetic analyses revealed tissue-specific effects: in normal lung, HDM enhanced pro-inflammatory and immune activation programs, whereas in tumors it suppressed T cell responses, antigen presentation, and chemokine signaling. Immune deconvolution showed a shift toward myeloid enrichment and lymphoid suppression, with reduced cytotoxic T and NK signatures. Notably, HDM-driven tumor promotion was abolished in <em>Il17a<sup>−/−</sup></em> but not <em>Il1b<sup>−/−</sup></em> mice, identifying IL-17A as a critical mediator. These findings demonstrate that chronic aeroallergen exposure reshapes the lung microenvironment to promote immune suppression and accelerate lung cancer progression.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101275"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-07DOI: 10.1016/j.neo.2026.101281
Mengli Gao , Yuge Ran , Juan Qi , Xiao Han , Yali Wei , Kunjie Wang , Xiaoxi Wu , Chengcheng Sun , Yanhong Li , Wenyan Wang , Wenjie Xie , Peng Zhang , Kuan Liu , Hongyun Shi
Background
Mast cells (MCs) are immunometabolic sentinels, yet their heterogeneity and functional specialization in breast cancer (BRCA) remain unclear. We hypothesized that arginine metabolism defines transcriptionally and functionally distinct MC subpopulations that shape the BRCA microenvironment.
Methods
We integrated single-cell RNA-seq (GSE161529; 272,592 cells, 38 clusters), spatial transcriptomics (GSE243022) and bulk RNA-seq (TCGA, GSE42568). After harmony batch-correction and Seurat–Louvian clustering, MCs were split by median arginine score (AUCell/UCell/AddModuleScore/singscore) into high- (HAS) and low-activity (LAS) subsets. Monocle2 pseudotime, CellChat, hdWGCNA (power = 15), LASSO-Cox and MiloR were used to trace differentiation, communication, prognostic value and triple-negative breast cancer (TNBC) enrichment. Functional validation of the model-prioritized gene OAT was subsequently conducted in clinical tissues and breast cancer cell lines through loss-of-function assays.
Results
HAS cells represented 18.7 % of all MCs and were enriched in TNBC (OR = 2.4, p < 0.001). They displayed higher differentiation potential (CytoTRACE: 0.72 vs 0.41, p < 0.001) and trajectory progression (pseudotime τ = 0.68). Arginine score correlated with differentiation (r = 0.52) and tumor risk signature (TRS, r = 0.35). CellChat revealed 1.8-fold increased incoming signals in HAS; VEGF and TGF-β pathways were most active (p < 0.001). hdWGCNA identified 19 modules; cyan and green modules (kME > 0.9) contained 214 HAS-up genes driving cell-cycle and arginine/glutamine metabolism. A five-gene (ARG1, NOS2, ASL, OAT, AZIN1) LASSO model predicted 5-year survival (AUC = 0.82; HR = 1.68, p < 0.001). Spatial maps confirmed ASL+ MC hotspots in tumor cores (AUC = 0.89 vs normal). Experimentally, OAT expression was elevated in TNBC tissues and cell lines. Knockdown of OAT impaired proliferation, induced apoptosis, suppressed migration/invasion, and modulated apoptosis- and EMT-related protein expression, functionally supporting its role in BRCA progression.
Conclusion
Arginine metabolism stratifies MCs into pro-tumorigenic HAS and quiescent LAS subsets; ASL-high MCs constitute a metabolically wired, highly communicating population that fuels TNBC progression and furnishes an exploitable prognostic signature. OAT, a key HAS-associated gene, promotes breast cancer aggressiveness through proliferation, survival, and invasion.
背景：肥大细胞（MCs）是免疫代谢的前哨细胞，但其在乳腺癌（BRCA）中的异质性和功能特化尚不清楚。我们假设精氨酸代谢定义了塑造BRCA微环境的转录和功能不同的MC亚群。方法：我们整合了单细胞RNA-seq （GSE161529; 272,592个细胞，38个簇）、空间转录组学（GSE243022）和整体RNA-seq （TCGA, GSE42568）。经过和谐批校正和Seurat-Louvian聚类，mc按精氨酸得分中位数（AUCell/UCell/AddModuleScore/singscore）划分为高活性（HAS）和低活性（LAS）子集。采用Monocle2 pseudotime、CellChat、hdWGCNA（幂值= 15）、LASSO-Cox和MiloR追踪分化、通讯、预后价值和三阴性乳腺癌（TNBC）富集情况。随后在临床组织和乳腺癌细胞系中通过功能丧失试验对模型优先基因OAT进行了功能验证。结果：HAS细胞占所有MCs的18.7%，在TNBC中富集（OR = 2.4, p < 0.001）。它们表现出更高的分化潜力（CytoTRACE: 0.72 vs 0.41, p < 0.001）和轨迹进展（伪时间τ = 0.68）。精氨酸评分与分化（r = 0.52）和肿瘤风险特征（TRS, r = 0.35）相关。CellChat显示HAS的输入信号增加了1.8倍；VEGF和TGF-β通路最活跃（p < 0.001）。hdWGCNA确定了19个模块；青色和绿色模块（kME > 0.9）含有214个驱动细胞周期和精氨酸/谷氨酰胺代谢的ha -up基因。5基因（ARG1、NOS2、ASL、OAT、AZIN1） LASSO模型预测5年生存率（AUC = 0.82; HR = 1.68, p < 0.001）。空间图证实肿瘤核心存在ASL+ MC热点（AUC = 0.89 vs正常）。实验中，OAT在TNBC组织和细胞系中的表达升高。OAT基因敲低会损害细胞增殖，诱导细胞凋亡，抑制迁移/侵袭，调节细胞凋亡和emt相关蛋白的表达，在功能上支持其在BRCA进展中的作用。结论：精氨酸代谢将MCs分为促肿瘤的HAS和静止的LAS亚群；asl高MCs构成了一个代谢连接，高度沟通的人群，促进TNBC的进展，并提供了一个可利用的预后标志。OAT是一个关键的has相关基因，通过增殖、存活和侵袭促进乳腺癌的侵袭性。
{"title":"Integrating single-cell and spatial transcriptomics to dissect mast-cell heterogeneity and arginine-metabolism-associated markers in BRCA","authors":"Mengli Gao , Yuge Ran , Juan Qi , Xiao Han , Yali Wei , Kunjie Wang , Xiaoxi Wu , Chengcheng Sun , Yanhong Li , Wenyan Wang , Wenjie Xie , Peng Zhang , Kuan Liu , Hongyun Shi","doi":"10.1016/j.neo.2026.101281","DOIUrl":"10.1016/j.neo.2026.101281","url":null,"abstract":"<div><h3>Background</h3><div>Mast cells (MCs) are immunometabolic sentinels, yet their heterogeneity and functional specialization in breast cancer (BRCA) remain unclear. We hypothesized that arginine metabolism defines transcriptionally and functionally distinct MC subpopulations that shape the BRCA microenvironment.</div></div><div><h3>Methods</h3><div>We integrated single-cell RNA-seq (GSE161529; 272,592 cells, 38 clusters), spatial transcriptomics (GSE243022) and bulk RNA-seq (TCGA, GSE42568). After harmony batch-correction and Seurat–Louvian clustering, MCs were split by median arginine score (AUCell/UCell/AddModuleScore/singscore) into high- (HAS) and low-activity (LAS) subsets. Monocle2 pseudotime, CellChat, hdWGCNA (power = 15), LASSO-Cox and MiloR were used to trace differentiation, communication, prognostic value and triple-negative breast cancer (TNBC) enrichment. Functional validation of the model-prioritized gene OAT was subsequently conducted in clinical tissues and breast cancer cell lines through loss-of-function assays.</div></div><div><h3>Results</h3><div>HAS cells represented 18.7 % of all MCs and were enriched in TNBC (OR = 2.4, p < 0.001). They displayed higher differentiation potential (CytoTRACE: 0.72 vs 0.41, p < 0.001) and trajectory progression (pseudotime τ = 0.68). Arginine score correlated with differentiation (r = 0.52) and tumor risk signature (TRS, r = 0.35). CellChat revealed 1.8-fold increased incoming signals in HAS; VEGF and TGF-β pathways were most active (p < 0.001). hdWGCNA identified 19 modules; cyan and green modules (kME > 0.9) contained 214 HAS-up genes driving cell-cycle and arginine/glutamine metabolism. A five-gene (ARG1, NOS2, ASL, OAT, AZIN1) LASSO model predicted 5-year survival (AUC = 0.82; HR = 1.68, p < 0.001). Spatial maps confirmed ASL<sup>+</sup> MC hotspots in tumor cores (AUC = 0.89 vs normal). Experimentally, OAT expression was elevated in TNBC tissues and cell lines. Knockdown of OAT impaired proliferation, induced apoptosis, suppressed migration/invasion, and modulated apoptosis- and EMT-related protein expression, functionally supporting its role in BRCA progression.</div></div><div><h3>Conclusion</h3><div>Arginine metabolism stratifies MCs into pro-tumorigenic HAS and quiescent LAS subsets; ASL-high MCs constitute a metabolically wired, highly communicating population that fuels TNBC progression and furnishes an exploitable prognostic signature. OAT, a key HAS-associated gene, promotes breast cancer aggressiveness through proliferation, survival, and invasion.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101281"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146143861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.neo.2025.101270
Bishi Wang, Kongxiu Wu, Xin Liu, Yuhai Shen, Yanliang Li
The advancement of novel pharmaceuticals and targeted therapeutic approaches is considerably obstructed by the insufficient comprehension of the intricate pathophysiology of colorectal cancer (CRC). The therapeutic effectiveness of tyrosine kinase inhibitors (TKI)-based systemic treatment for advanced CRC is limited by medication resistance. Research has revealed that therapeutic strategies aimed at the myosin light chain kinase family member 4 (MYLK4) and its corresponding response element can suppress tumour proliferation and yield significant clinical advantages for cancer patients. This study reveals that MYLK4-mediated lipid metabolic reprogramming confers resistance to TKI-induced ferroptosis in CRC. MYLK4 directly interacts with tripartite motif containing 15 (TRIM15) in a way reliant on mouse double minute 2 homolog (MDM2), hence enhancing p53 ubiquitination and degradation. Significantly, p53 suppresses the transcription of stearoyl-CoA desaturase 1 (SCD1) through binding to its promoter. Elevated SCD1 levels correlate with increased MYLK4 levels, and their concurrent expression forecasts regorafenib resistance and poor prognosis in colorectal cancer. Regorafenib and SCD1 inhibitor (SCD1 inhibitor-3) co-treatment demonstrate promising anti-tumor efficacy in organoids and xenografted tumours derived from wild-type p53 colorectal cancer patients. Patients with colorectal cancer exhibiting elevated MYLK4 activity and wild-type p53 may derive clinical benefits from this combination therapy. These results suggest that MYLK4 may serve as a promising therapeutic target for the treatment of colorectal cancer.
{"title":"MYLK4 promotes colorectal cancer progression by regulating lipid metabolism reprogramming via targeting ferroptosis","authors":"Bishi Wang, Kongxiu Wu, Xin Liu, Yuhai Shen, Yanliang Li","doi":"10.1016/j.neo.2025.101270","DOIUrl":"10.1016/j.neo.2025.101270","url":null,"abstract":"<div><div>The advancement of novel pharmaceuticals and targeted therapeutic approaches is considerably obstructed by the insufficient comprehension of the intricate pathophysiology of colorectal cancer (CRC). The therapeutic effectiveness of tyrosine kinase inhibitors (TKI)-based systemic treatment for advanced CRC is limited by medication resistance. Research has revealed that therapeutic strategies aimed at the myosin light chain kinase family member 4 (MYLK4) and its corresponding response element can suppress tumour proliferation and yield significant clinical advantages for cancer patients. This study reveals that MYLK4-mediated lipid metabolic reprogramming confers resistance to TKI-induced ferroptosis in CRC. MYLK4 directly interacts with tripartite motif containing 15 (TRIM15) in a way reliant on mouse double minute 2 homolog (MDM2), hence enhancing p53 ubiquitination and degradation. Significantly, p53 suppresses the transcription of stearoyl-CoA desaturase 1 (SCD1) through binding to its promoter. Elevated SCD1 levels correlate with increased MYLK4 levels, and their concurrent expression forecasts regorafenib resistance and poor prognosis in colorectal cancer. Regorafenib and SCD1 inhibitor (SCD1 inhibitor-3) co-treatment demonstrate promising anti-tumor efficacy in organoids and xenografted tumours derived from wild-type p53 colorectal cancer patients. Patients with colorectal cancer exhibiting elevated MYLK4 activity and wild-type p53 may derive clinical benefits from this combination therapy. These results suggest that MYLK4 may serve as a promising therapeutic target for the treatment of colorectal cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101270"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146057605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-14DOI: 10.1016/j.neo.2026.101287
Junjie Nie , Xinwei Liu , Mu Xu , Xinliang Gu , Shangshang Hu , Huiling Sun , Linpeng Zhou , Tao Xu , Yuqin Pan , Shukui Wang
Background
Metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the molecular regulators that orchestrate this process remain incompletely understood. Although many long non-coding RNAs (lncRNAs) possess protein-coding potential, their translational products and metabolic functions have been largely overlooked. Here, we identify MUCP1, a microprotein encoded by the lncRNA MUC20-OT1, as a critical regulator of mitochondrial metabolism and epigenetic remodeling in CRC.
Methods
Multi-omics data were integrated to identify MUC20-OT1 as a candidate lncRNA encoding a functional microprotein. Fusion reporter plasmids, mass spectrometry, and immunoblotting were used to validate MUCP1 translation and mitochondrial localization. Functional assays, metabolomic profiling, 13C5-glutamine isotope tracing, subcellular succinate quantification, CUT&Tag, and xenograft models were performed to investigate the role of MUCP1 in facilitating mitochondrial succinate export and maintaining glutamine metabolism homeostasis.
Results
The microprotein MUCP1, encoded by the lncRNA MUC20-OT1, serves as an auxiliary regulator of SLC25A10-mediated mitochondrial succinate transport. MUCP1 is upregulated during CRC progression and localizes in the mitochondrial outer membrane, where it facilitates the balance of mitochondrial succinate metabolism. Elevated extramitochondrial succinate subsequently enhances H3K4me3 histone modifications, promoting the transcription of enzymes involved in glutamine metabolism and sustaining the high metabolic demands of CRC cells.
Conclusions
This study identifies MUCP1 as a novel lncRNA-encoded microprotein that maintains metabolic homeostasis in CRC by coupling mitochondrial succinate transport to histone methylation. MUCP1 might be a promising metabolic vulnerability and therapeutic target in CRC.
{"title":"A novel microprotein MUCP1 promotes colorectal cancer metabolic reprogramming by regulating mitochondrial succinate transport","authors":"Junjie Nie , Xinwei Liu , Mu Xu , Xinliang Gu , Shangshang Hu , Huiling Sun , Linpeng Zhou , Tao Xu , Yuqin Pan , Shukui Wang","doi":"10.1016/j.neo.2026.101287","DOIUrl":"10.1016/j.neo.2026.101287","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic reprogramming is a hallmark of colorectal cancer (CRC), yet the molecular regulators that orchestrate this process remain incompletely understood. Although many long non-coding RNAs (lncRNAs) possess protein-coding potential, their translational products and metabolic functions have been largely overlooked. Here, we identify MUCP1, a microprotein encoded by the lncRNA MUC20-OT1, as a critical regulator of mitochondrial metabolism and epigenetic remodeling in CRC.</div></div><div><h3>Methods</h3><div>Multi-omics data were integrated to identify MUC20-OT1 as a candidate lncRNA encoding a functional microprotein. Fusion reporter plasmids, mass spectrometry, and immunoblotting were used to validate MUCP1 translation and mitochondrial localization. Functional assays, metabolomic profiling, <sup>13</sup>C<sub>5</sub>-glutamine isotope tracing, subcellular succinate quantification, CUT&Tag, and xenograft models were performed to investigate the role of MUCP1 in facilitating mitochondrial succinate export and maintaining glutamine metabolism homeostasis.</div></div><div><h3>Results</h3><div>The microprotein MUCP1, encoded by the lncRNA MUC20-OT1, serves as an auxiliary regulator of SLC25A10-mediated mitochondrial succinate transport. MUCP1 is upregulated during CRC progression and localizes in the mitochondrial outer membrane, where it facilitates the balance of mitochondrial succinate metabolism. Elevated extramitochondrial succinate subsequently enhances H3K4me3 histone modifications, promoting the transcription of enzymes involved in glutamine metabolism and sustaining the high metabolic demands of CRC cells.</div></div><div><h3>Conclusions</h3><div>This study identifies MUCP1 as a novel lncRNA-encoded microprotein that maintains metabolic homeostasis in CRC by coupling mitochondrial succinate transport to histone methylation. MUCP1 might be a promising metabolic vulnerability and therapeutic target in CRC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101287"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-12DOI: 10.1016/j.neo.2026.101285
Shuaike Qu , Zhihao Liu , Beibei Wang , Xin Li , Zhongbo Li , Yingwen Gai , Yanan Sun , Qi Zhang , Yaguang Sun , Wei Pan , Jian Zhu , Xiaodong Tan
The over-activation of Hippo/YAP axis was often observed in pancreatic adenocarcinoma (PAAD), while the detailed mechanism is not totally understood. Recent studies demonstrated that the ubiquitin modification, which controlled the protein stability of YAP, played important roles in Hippo signaling and PAAD progression. In order to understand the underlying link between YAP protein stability and Hippo activity in PAAD progression, we carried out GSEA bioinformatic analysis coupled with siRNA screening and identified OTUD4 as an important effector for Hippo signaling in PAAD. OTUD4, which was highly expressed in PAAD tissue, correlated with Hippo target gene expression in PAAD tissues. Depletion of OTUD4 significantly reduced the activity of Hippo/YAP axis and hampered PAAD progression. Mechanism studies revealed that OTUD4 could interact with YAP and promote YAP K48-linked poly-ubiquitination and degradation in PAAD. In conclusion, our study identified an interesting regulation mechanism between OTUD4 and Hippo signaling in PAAD, while targeting OTUD4 could be a plausible strategy for PAAD therapy.
Abbreviation: OTUD4, OTU Domain-Containing Protein 4; YAP, Yes-Associated Protein; TEAD, Transcriptional Enhanced Associate Domain transcriptional factor; TCGA, The Cancer Genome Atlas; ATCC, American Type Culture Collection; DMEM, Dulbecco’s Modified Eagle Medium; DUB, Deubiquitinase; GSEA, Gene Set Enrichment Analysis; NES, Normalized Enrichment Score; ECL, Enhanced Chemiluminescence; PVDF, Polyvinylidene Fluoride; PMSF, Phenyl Methane Sulfonyl Fluoride; PFA, Paraformaldehyde; Co-IP, Coimmunoprecipitation; IHC, Immunohistochemistry; CHX, Cycloheximide; IF, Immunofluorescence; GEO, Gene Expression Omnibus
{"title":"OTUD4 regulates pancreatic cancer progression via Hippo/YAP axis","authors":"Shuaike Qu , Zhihao Liu , Beibei Wang , Xin Li , Zhongbo Li , Yingwen Gai , Yanan Sun , Qi Zhang , Yaguang Sun , Wei Pan , Jian Zhu , Xiaodong Tan","doi":"10.1016/j.neo.2026.101285","DOIUrl":"10.1016/j.neo.2026.101285","url":null,"abstract":"<div><div>The over-activation of Hippo/YAP axis was often observed in pancreatic adenocarcinoma (PAAD), while the detailed mechanism is not totally understood. Recent studies demonstrated that the ubiquitin modification, which controlled the protein stability of YAP, played important roles in Hippo signaling and PAAD progression. In order to understand the underlying link between YAP protein stability and Hippo activity in PAAD progression, we carried out GSEA bioinformatic analysis coupled with siRNA screening and identified OTUD4 as an important effector for Hippo signaling in PAAD. OTUD4, which was highly expressed in PAAD tissue, correlated with Hippo target gene expression in PAAD tissues. Depletion of OTUD4 significantly reduced the activity of Hippo/YAP axis and hampered PAAD progression. Mechanism studies revealed that OTUD4 could interact with YAP and promote YAP K48-linked poly-ubiquitination and degradation in PAAD. In conclusion, our study identified an interesting regulation mechanism between OTUD4 and Hippo signaling in PAAD, while targeting OTUD4 could be a plausible strategy for PAAD therapy.</div><div><strong>Abbreviation:</strong> OTUD4, OTU Domain-Containing Protein 4; YAP, Yes-Associated Protein; TEAD, Transcriptional Enhanced Associate Domain transcriptional factor; TCGA, The Cancer Genome Atlas; ATCC, American Type Culture Collection; DMEM, Dulbecco’s Modified Eagle Medium; DUB, Deubiquitinase; GSEA, Gene Set Enrichment Analysis; NES, Normalized Enrichment Score; ECL, Enhanced Chemiluminescence; PVDF, Polyvinylidene Fluoride; PMSF, Phenyl Methane Sulfonyl Fluoride; PFA, Paraformaldehyde; Co-IP, Coimmunoprecipitation; IHC, Immunohistochemistry; CHX, Cycloheximide; IF, Immunofluorescence; GEO, Gene Expression Omnibus</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"73 ","pages":"Article 101285"},"PeriodicalIF":7.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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