Pub Date : 2026-01-06DOI: 10.1016/j.neo.2025.101267
Chengyuan Xu , Tengfei Li , Lin Zhang , Qin Zhang , Shanshan Cai , Qiangqiang Fu , Siqi Zhang
Background
Cancer-associated fibroblasts (CAFs) critically influence colorectal cancer (CRC) progression and therapy response, yet their epidemiological and molecular heterogeneity remains underexplored.
Methods
We integrated bulk, single-cell, and spatial transcriptomic datasets from multiple CRC cohorts, together with patient-derived tissues and functional assays, to delineate CAF subtypes and their clinical significance. Epidemiological analyses were performed across independent cohorts to evaluate the association between CAF markers and patient outcomes.
Results
A myofibroblastic CAF (myCAF) subset characterized by high LOXL2 expression was consistently enriched in advanced and chemoresistant CRC samples. Multi-omics correlation analyses revealed that LOXL2⁺ CAFs activated WNT signaling in adjacent tumor cells, promoting stemness and drug resistance. Across population-based cohorts, elevated LOXL2 expression was independently associated with poor overall and disease-free survival, as confirmed by multivariate Cox regression. Spatial transcriptomics and immunofluorescence demonstrated close physical interaction between LOXL2⁺ CAFs and WNT5A-positive cancer cells. Functional inhibition or genetic silencing of LOXL2 and wnt5a in CAFs restored chemosensitivity in vitro and suppressed tumor growth in vivo.
Conclusions
Our integrative epidemiological and experimental analyses identify LOXL2⁺ CAFs as a key stromal determinant of chemoresistance and poor prognosis in CRC. These findings highlight a clinically relevant stromal biomarker with potential for risk stratification and therapeutic targeting in colorectal cancer.
{"title":"LOXL2⁺ cancer-associated fibroblasts shape WNT signaling to drive chemoresistance and poor outcomes in colorectal cancer: Insights from multi-omics and epidemiological analyses","authors":"Chengyuan Xu , Tengfei Li , Lin Zhang , Qin Zhang , Shanshan Cai , Qiangqiang Fu , Siqi Zhang","doi":"10.1016/j.neo.2025.101267","DOIUrl":"10.1016/j.neo.2025.101267","url":null,"abstract":"<div><h3>Background</h3><div>Cancer-associated fibroblasts (CAFs) critically influence colorectal cancer (CRC) progression and therapy response, yet their epidemiological and molecular heterogeneity remains underexplored.</div></div><div><h3>Methods</h3><div>We integrated bulk, single-cell, and spatial transcriptomic datasets from multiple CRC cohorts, together with patient-derived tissues and functional assays, to delineate CAF subtypes and their clinical significance. Epidemiological analyses were performed across independent cohorts to evaluate the association between CAF markers and patient outcomes.</div></div><div><h3>Results</h3><div>A myofibroblastic CAF (myCAF) subset characterized by high LOXL2 expression was consistently enriched in advanced and chemoresistant CRC samples. Multi-omics correlation analyses revealed that LOXL2⁺ CAFs activated WNT signaling in adjacent tumor cells, promoting stemness and drug resistance. Across population-based cohorts, elevated LOXL2 expression was independently associated with poor overall and disease-free survival, as confirmed by multivariate Cox regression. Spatial transcriptomics and immunofluorescence demonstrated close physical interaction between LOXL2⁺ CAFs and WNT5A-positive cancer cells. Functional inhibition or genetic silencing of LOXL2 and wnt5a in CAFs restored chemosensitivity <em>in vitro</em> and suppressed tumor growth <em>in vivo</em>.</div></div><div><h3>Conclusions</h3><div>Our integrative epidemiological and experimental analyses identify LOXL2⁺ CAFs as a key stromal determinant of chemoresistance and poor prognosis in CRC. These findings highlight a clinically relevant stromal biomarker with potential for risk stratification and therapeutic targeting in colorectal cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101267"},"PeriodicalIF":7.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913772","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 : 2025-12-17DOI: 10.1016/j.neo.2025.101264
Anli Lai , Wenbing Liu , Yihan Mei, Qimin Zhang, Junping Zhang, Kejing Tang, Qing Rao, Runxia Gu, Sizhou Feng, Ying Wang, Min Wang, Hui Wei, Yingchang Mi, Shaowei Qiu, Jianxiang Wang
Acute myeloid leukemia (AML) is characterized by the sequential accumulation of genetic mutations in hematopoietic stem/progenitor cells (HSPCs). The FLT3-ITD mutation, occurring in 20-30 % of AML cases, typically emerges as a late event. Despite its established association with adverse prognosis, significant outcome heterogeneity persists in FLT3-ITD AML. The clonal origin of FLT3-ITD may serve as a critical determinant of phenotypic and prognostic variability, though the underlying mechanisms remain poorly understood. This study enrolled 149 FLT3-ITD AML patients. Genomic and transcriptomic profiling defined four prognostic origin subtypes (DNMT3A/NPM1-mutation, IDH/NPM1-mutation, transcription factor [TF]-related lesion and other genetic lesion origin). Within the high risk DNMT3A/NPM1-origin subgroup, stratification by differentiation state showed hematopoietic stem cell arrest conferred an inferior event-free survival compared with arrest at the monocyte stage. Analysis of refractory/relapsed (R/R) cases revealed the prevalence of baseline 13q uniparental dismoy (UPD) in DNMT3A/NPM1-origin subgroup. All DNMT3A/NPM1-origin patients acquired 13q UPD at the R/R stage, arising from either expansion of pre-existing UPD subclones or de novo UPD acquisition under therapeutic pressure. Single-cell analysis further revealed aberrant activation of the DNA homologous recombination repair in DNMT3A/NPM1-origin patient blasts and triple-mutant mouse HSPCs. In conclusion, FLT3-ITD clonal origin demonstrated significant impact on the outcome of AML. Acquired 13q UPD drives clonal evolution and disease progression in the DNMT3A/NPM1-origin subgroup, highlighting its potential as a therapeutic target.
{"title":"Clonal architecture of FLT3-ITD and acquired 13q uniparental disomy define prognostic heterogeneity and therapeutic vulnerabilities in acute myeloid leukemia","authors":"Anli Lai , Wenbing Liu , Yihan Mei, Qimin Zhang, Junping Zhang, Kejing Tang, Qing Rao, Runxia Gu, Sizhou Feng, Ying Wang, Min Wang, Hui Wei, Yingchang Mi, Shaowei Qiu, Jianxiang Wang","doi":"10.1016/j.neo.2025.101264","DOIUrl":"10.1016/j.neo.2025.101264","url":null,"abstract":"<div><div>Acute myeloid leukemia (AML) is characterized by the sequential accumulation of genetic mutations in hematopoietic stem/progenitor cells (HSPCs). The <em>FLT3</em>-ITD mutation, occurring in 20-30 % of AML cases, typically emerges as a late event. Despite its established association with adverse prognosis, significant outcome heterogeneity persists in <em>FLT3</em>-ITD AML. The clonal origin of <em>FLT3</em>-ITD may serve as a critical determinant of phenotypic and prognostic variability, though the underlying mechanisms remain poorly understood. This study enrolled 149 <em>FLT3</em>-ITD AML patients. Genomic and transcriptomic profiling defined four prognostic origin subtypes (<em>DNMT3A</em>/<em>NPM1</em>-mutation, <em>IDH</em>/<em>NPM1</em>-mutation, transcription factor [TF]-related lesion and other genetic lesion origin). Within the high risk <em>DNMT3A</em>/<em>NPM1</em>-origin subgroup, stratification by differentiation state showed hematopoietic stem cell arrest conferred an inferior event-free survival compared with arrest at the monocyte stage. Analysis of refractory/relapsed (R/R) cases revealed the prevalence of baseline 13q uniparental dismoy (UPD) in <em>DNMT3A</em>/<em>NPM1</em>-origin subgroup. All <em>DNMT3A</em>/<em>NPM1</em>-origin patients acquired 13q UPD at the R/R stage, arising from either expansion of pre-existing UPD subclones or de novo UPD acquisition under therapeutic pressure. Single-cell analysis further revealed aberrant activation of the DNA homologous recombination repair in <em>DNMT3A</em>/<em>NPM1</em>-origin patient blasts and triple-mutant mouse HSPCs. In conclusion, <em>FLT3</em>-ITD clonal origin demonstrated significant impact on the outcome of AML. Acquired 13q UPD drives clonal evolution and disease progression in the <em>DNMT3A</em>/<em>NPM1</em>-origin subgroup, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101264"},"PeriodicalIF":7.7,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145783511","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 : 2025-12-11DOI: 10.1016/j.neo.2025.101263
Federica Lorenzi , Matthew Shipley , Luke Deane , Robert Goldstone , Vidur Tandon , Barbara Martins da Costa , Kevin Greenslade , Karen Barker , Fariba Nemati , Angela Bellini , Gudrun Schleiermacher , Louis Chesler , Francois Guillemot , Sally L George
Neuroblastoma is a childhood cancer, arising in the developing sympathetic nervous system. Differentiation therapy with 13-cis-retinoic acid (RA) is given to children with neuroblastoma to prevent relapse, however there is little understanding of which patients benefit. ATRX alterations are identified in 10 % of high-risk neuroblastomas and associated with poor outcomes. The commonest type of ATRX alterations in neuroblastoma are in-frame multi-exon deletions, followed by nonsense mutations predicted to result in loss-of-function (ATRX LoF).
We treated paired ATRX wild-type and LoF neuroblastoma cell-lines with RA: cells with ATRX LoF fail to upregulate direct RA target genes and show reduced chromatin accessibility differentiation and development related genes following RA treatment. Conversely, neuroblastoma models with in-frame deletions mount an appropriate epigenetic response to RA. Taken together this shows that the mechanism of differentiation in ATRX-altered neuroblastoma depends on the type of ATRX alteration, with implications relating to both oncogenesis and therapeutic response.
{"title":"Differential chromatin accessibility response to retinoic acid in neuroblastoma with ATRX in-frame-deletions versus ATRX loss-of-function","authors":"Federica Lorenzi , Matthew Shipley , Luke Deane , Robert Goldstone , Vidur Tandon , Barbara Martins da Costa , Kevin Greenslade , Karen Barker , Fariba Nemati , Angela Bellini , Gudrun Schleiermacher , Louis Chesler , Francois Guillemot , Sally L George","doi":"10.1016/j.neo.2025.101263","DOIUrl":"10.1016/j.neo.2025.101263","url":null,"abstract":"<div><div>Neuroblastoma is a childhood cancer, arising in the developing sympathetic nervous system. Differentiation therapy with 13-cis-retinoic acid (RA) is given to children with neuroblastoma to prevent relapse, however there is little understanding of which patients benefit. <em>ATRX</em> alterations are identified in 10 % of high-risk neuroblastomas and associated with poor outcomes. The commonest type of <em>ATRX</em> alterations in neuroblastoma are in-frame multi-exon deletions, followed by nonsense mutations predicted to result in loss-of-function (<em>ATRX</em> LoF).</div><div>We treated paired <em>ATRX</em> wild-type and LoF neuroblastoma cell-lines with RA: cells with <em>ATRX</em> LoF fail to upregulate direct RA target genes and show reduced chromatin accessibility differentiation and development related genes following RA treatment. Conversely, neuroblastoma models with in-frame deletions mount an appropriate epigenetic response to RA. Taken together this shows that the mechanism of differentiation in <em>ATRX</em>-altered neuroblastoma depends on the type of <em>ATRX</em> alteration, with implications relating to both oncogenesis and therapeutic response.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101263"},"PeriodicalIF":7.7,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145745268","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 : 2025-12-08DOI: 10.1016/j.neo.2025.101262
Blair P. Rendina , Fahim Ahmad , Luka Akerman , Ian Mills , Nina C. Lee , Chixiang Chen , Haoyu Ren , Xiaoxuan Fan , Jeffrey A. Winkles , Graeme F. Woodworth , Gerald M. Wilson , Eli E. Bar
MBNL1 binds the HIF-1α 3′UTR to promote rapid mRNA decay, thereby limiting HIF-1 activity and hypoxia-induced stemness in glioblastoma. Using patient-derived glioma stem cells, we show that MBNL1 loss stabilizes HIF-1α mRNA and increases HIF-1α protein, HRE reporter activity, and target gene expression under hypoxia; MBNL1 knockout also prolongs target gene expression after reoxygenation, indicating enhanced hypoxia “memory.” MBNL1 depletion markedly elevates stemness markers (KLF4, SOX2, GLI1) and clonogenic growth, and re-expression of MBNL1 reverses these effects. These results identify a post-transcriptional MBNL1–HIF1α axis that controls hypoxia signaling and stemness, with implications for GBM therapy.
{"title":"Post-transcriptional control of HIF-1α by MBNL1 restrains hypoxia-driven stemness in GBM","authors":"Blair P. Rendina , Fahim Ahmad , Luka Akerman , Ian Mills , Nina C. Lee , Chixiang Chen , Haoyu Ren , Xiaoxuan Fan , Jeffrey A. Winkles , Graeme F. Woodworth , Gerald M. Wilson , Eli E. Bar","doi":"10.1016/j.neo.2025.101262","DOIUrl":"10.1016/j.neo.2025.101262","url":null,"abstract":"<div><div>MBNL1 binds the HIF-1α 3′UTR to promote rapid mRNA decay, thereby limiting HIF-1 activity and hypoxia-induced stemness in glioblastoma. Using patient-derived glioma stem cells, we show that MBNL1 loss stabilizes HIF-1α mRNA and increases HIF-1α protein, HRE reporter activity, and target gene expression under hypoxia; MBNL1 knockout also prolongs target gene expression after reoxygenation, indicating enhanced hypoxia “memory.” MBNL1 depletion markedly elevates stemness markers (KLF4, SOX2, GLI1) and clonogenic growth, and re-expression of MBNL1 reverses these effects. These results identify a post-transcriptional MBNL1–HIF1α axis that controls hypoxia signaling and stemness, with implications for GBM therapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101262"},"PeriodicalIF":7.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145697766","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}
Intratumoral heterogeneity contributes to therapy resistance and immune evasion in breast cancer, making treatment strategies more complex. This study integrates single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq deconvolution to characterize tumor subpopulations and develop a robust prognostic model.
Methods
We employed a multi-omics approach combining scRNA-seq, spatial transcriptomics, and bulk RNA-seq data deconvolution to explore the molecular diversity within breast cancer tumors. Tumor subtypes were identified based on distinct gene expression profiles, and functional pathway analysis was conducted to evaluate associations with clinical outcomes, including therapy resistance and immune evasion. Data from TCGA and GEO cohorts were integrated to validate the prognostic and immune-related findings. A CoxBoost+GBM algorithm was used to develop a robust prognostic model for patient survival and immunotherapy response prediction.
Results
Five distinct tumor subtypes were identified, each with unique functional profiles, underscoring the complexity of breast cancer heterogeneity. Basal-like breast cancer (BLBC) cells were found to play a central role in immune evasion and poor immunotherapy response, with high basal-like cell infiltration correlating with worse survival outcomes. Spatial transcriptomics revealed the widespread presence of BLBC cells across clinical subtypes, including ER+ tumors, suggesting their involvement in therapy resistance. A prognostic model based on CoxBoost+GBM demonstrated strong predictive power for patient survival and immunotherapy efficacy.
Conclusions
This study provides a comprehensive view of the genetic and immune determinants of breast cancer heterogeneity, with a focus on BLBC’s role in immune escape and treatment resistance. These insights enhance the potential of multi-omics approaches in precision prevention, early detection, and personalized immunotherapy strategies.
{"title":"Multi-omics analysis unveils tumor heterogeneity and immunotherapy predictive model in breast cancer for precision medicine and early detection","authors":"Zhenxiong Zhao , Zhencang Zheng , Shenglu Jiang , Lingling Zhang , Xiufeng Tang","doi":"10.1016/j.neo.2025.101260","DOIUrl":"10.1016/j.neo.2025.101260","url":null,"abstract":"<div><h3>Background</h3><div>Intratumoral heterogeneity contributes to therapy resistance and immune evasion in breast cancer, making treatment strategies more complex. This study integrates single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq deconvolution to characterize tumor subpopulations and develop a robust prognostic model.</div></div><div><h3>Methods</h3><div>We employed a multi-omics approach combining scRNA-seq, spatial transcriptomics, and bulk RNA-seq data deconvolution to explore the molecular diversity within breast cancer tumors. Tumor subtypes were identified based on distinct gene expression profiles, and functional pathway analysis was conducted to evaluate associations with clinical outcomes, including therapy resistance and immune evasion. Data from TCGA and GEO cohorts were integrated to validate the prognostic and immune-related findings. A CoxBoost+GBM algorithm was used to develop a robust prognostic model for patient survival and immunotherapy response prediction.</div></div><div><h3>Results</h3><div>Five distinct tumor subtypes were identified, each with unique functional profiles, underscoring the complexity of breast cancer heterogeneity. Basal-like breast cancer (BLBC) cells were found to play a central role in immune evasion and poor immunotherapy response, with high basal-like cell infiltration correlating with worse survival outcomes. Spatial transcriptomics revealed the widespread presence of BLBC cells across clinical subtypes, including ER+ tumors, suggesting their involvement in therapy resistance. A prognostic model based on CoxBoost+GBM demonstrated strong predictive power for patient survival and immunotherapy efficacy.</div></div><div><h3>Conclusions</h3><div>This study provides a comprehensive view of the genetic and immune determinants of breast cancer heterogeneity, with a focus on BLBC’s role in immune escape and treatment resistance. These insights enhance the potential of multi-omics approaches in precision prevention, early detection, and personalized immunotherapy strategies.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101260"},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679202","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 : 2025-12-03DOI: 10.1016/j.neo.2025.101261
Yan Li , Yanmin Wu , Liyan Liang , Xufeng Yao , Yiyang Pan , Lurong Zhang , Yaxin Wang , Jian Zhang , Kwan T Chow , Chunwan Lu
It has been extensively studied that IFN-I inhibits tumor progression through their intrinsic functions in tumor cells, of which, regulating tumor cell immunogenicity is a critical way. Besides to tumor cells, myeloid cells also comprise a major component of tumor microenvironment. Nevertheless, whether IFN-I modulates the immunogenicity and function of myeloid cells in tumor microenvironment is less explored. In this research, we report that IFNβ effectively induces Ly6C+ myeloid cell differentiation in vitro in mouse. In human PBMCs, CD14+CD33+ monocytic population was consistently accumulated in the presence of IFNβ. In agreement, overexpression of IFNβ in tumor microenvironment by IFNBCOL01 treatment resulted in dramatic increase of tumor-infiltrating Ly6C+ myeloid cells and obvious tumor growth control in vivo. Of note, overexpression of IFNβ promotes the immunogenic Ly6C+CD103+CD11c+ subset accumulation in tumor-infiltrating myeloid cells. At the molecular level, we illustrated that the pSTAT1 directly binds to the irf1 promoter and that IRF1 directly binds to the Ly6C promoter in myeloid cells both in vitro and in vivo. Furthermore, anti-Ly6C blockade therapy significantly reversed the anti-tumor effect of IFNBCOL01 by restoring NOS2 expression and consequently suppressing T cell functions in tumor-bearing mice. Overall, our findings determine that IFNβ drives myeloid cells to differentiate into Ly6C+ subset via the stimulation of pSTAT1-IRF1 axis in myeloid cells. In addition, IFNβ inhibits the immunosuppressive enzyme NOS2 expression in Ly6C+ myeloid cells, which may decrease the potential immunosuppressive function of NOS2 to boost the T cell function to repress tumor, thus proposing a new perspective for the anti-tumor mechanism of IFN-I.
{"title":"IFNβ−pSTAT1-IRF1 axis controls colorectal tumor development through induction of immunogenic Ly6C+myeloid cells","authors":"Yan Li , Yanmin Wu , Liyan Liang , Xufeng Yao , Yiyang Pan , Lurong Zhang , Yaxin Wang , Jian Zhang , Kwan T Chow , Chunwan Lu","doi":"10.1016/j.neo.2025.101261","DOIUrl":"10.1016/j.neo.2025.101261","url":null,"abstract":"<div><div>It has been extensively studied that IFN-I inhibits tumor progression through their intrinsic functions in tumor cells, of which, regulating tumor cell immunogenicity is a critical way. Besides to tumor cells, myeloid cells also comprise a major component of tumor microenvironment. Nevertheless, whether IFN-I modulates the immunogenicity and function of myeloid cells in tumor microenvironment is less explored. In this research, we report that IFNβ effectively induces Ly6C<sup>+</sup> myeloid cell differentiation in vitro in mouse. In human PBMCs, CD14<sup>+</sup>CD33<sup>+</sup> monocytic population was consistently accumulated in the presence of IFNβ. In agreement, overexpression of IFNβ in tumor microenvironment by IFNBCOL01 treatment resulted in dramatic increase of tumor-infiltrating Ly6C<sup>+</sup> myeloid cells and obvious tumor growth control in vivo. Of note, overexpression of IFNβ promotes the immunogenic Ly6C<sup>+</sup>CD103<sup>+</sup>CD11c<sup>+</sup> subset accumulation in tumor-infiltrating myeloid cells. At the molecular level, we illustrated that the pSTAT1 directly binds to the <em>irf1</em> promoter and that IRF1 directly binds to the <em>Ly6C</em> promoter in myeloid cells both in vitro and in vivo. Furthermore, anti-Ly6C blockade therapy significantly reversed the anti-tumor effect of IFNBCOL01 by restoring NOS2 expression and consequently suppressing T cell functions in tumor-bearing mice. Overall, our findings determine that IFNβ drives myeloid cells to differentiate into Ly6C<sup>+</sup> subset via the stimulation of pSTAT1-IRF1 axis in myeloid cells. In addition, IFNβ inhibits the immunosuppressive enzyme NOS2 expression in Ly6C<sup>+</sup> myeloid cells, which may decrease the potential immunosuppressive function of NOS2 to boost the T cell function to repress tumor, thus proposing a new perspective for the anti-tumor mechanism of IFN-I.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101261"},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145679180","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 : 2025-11-28DOI: 10.1016/j.neo.2025.101258
Michael Sergeev , Melanie A. Meier , Petra Wohlleben , Laura Rupprecht , Mirka Kupraszewicz-Hutzler , Karl Hilgers , Andrea Hartner , Anna-Lena Voegele , Raja Atreya , Yannick Frey , Showmika Srirangan , Jutta Eichler , Caroline Confais , Benoît Hédan , Ulrich Jarry , Monilola A. Olayioye , Susanne Muehlich
Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) in vitro and in vivo in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.
{"title":"Filamin a binds deleted in liver cancer 1 (DLC1) to promote its tumor suppressor activity and inhibit the SRF coactivator MRTF-A","authors":"Michael Sergeev , Melanie A. Meier , Petra Wohlleben , Laura Rupprecht , Mirka Kupraszewicz-Hutzler , Karl Hilgers , Andrea Hartner , Anna-Lena Voegele , Raja Atreya , Yannick Frey , Showmika Srirangan , Jutta Eichler , Caroline Confais , Benoît Hédan , Ulrich Jarry , Monilola A. Olayioye , Susanne Muehlich","doi":"10.1016/j.neo.2025.101258","DOIUrl":"10.1016/j.neo.2025.101258","url":null,"abstract":"<div><div>Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) <em>in vitro</em> and <em>in vivo</em> in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101258"},"PeriodicalIF":7.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620907","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 : 2025-11-25DOI: 10.1016/j.neo.2025.101259
Bing Liang , Annan Hu , Hongwei Lu , Hao Zhou , Qing Chen , Chao Jia , Jinjin Wang , Libo Jiang , Wei Hong , Jian Zhou , Jian Dong
Triple-negative breast cancer (TNBC) exhibits a high propensity for spinal metastasis, leading to severe morbidity and limited therapeutic responses. However, the molecular mechanisms driving spinal colonization remain poorly defined. Here, we identify the epigenetic reader ZMYND8 as a key mediator of TNBC spinal metastasis. ZMYND8 is significantly upregulated in spinal metastatic lesions and correlates with adverse patient outcomes. Transcriptomic profiling reveals that spinal metastases display profoundly immunosuppressive microenvironments, with elevated M2 macrophage infiltration positively associated with ZMYND8 expression. Mechanistically, ZMYND8 functions as a scaffold protein that promotes assembly of the DDX3X–CK1ε complex, thereby activating WNT/β-catenin signaling and promoting spinal metastasis. Furthermore, we identify OTUD4 as a bona fide deubiquitinase that directly interacts with and stabilizes ZMYND8, thereby enhancing TNBC cell migration, invasion, and spinal colonization. The resulting OTUD4–ZMYND8–DDX3X signaling axis drives canonical WNT/β-catenin signaling, upregulates CSF1 expression and promotes M2 polarization of macrophages, collectively fostering invasive behavior and establishing an immunosuppressive niche conducive to spinal metastasis. Collectively, these findings establish the OTUD4–ZMYND8–DDX3X axis as a pivotal regulator of spinal metastasis in TNBC and highlight its potential as a therapeutic target for inhibiting metastatic progression.
{"title":"OTUD4-ZMYND8-DDX3X Axis Drives Immunosuppressive Microenvironment in Spinal Metastases of Triple-Negative Breast Cancer","authors":"Bing Liang , Annan Hu , Hongwei Lu , Hao Zhou , Qing Chen , Chao Jia , Jinjin Wang , Libo Jiang , Wei Hong , Jian Zhou , Jian Dong","doi":"10.1016/j.neo.2025.101259","DOIUrl":"10.1016/j.neo.2025.101259","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) exhibits a high propensity for spinal metastasis, leading to severe morbidity and limited therapeutic responses. However, the molecular mechanisms driving spinal colonization remain poorly defined. Here, we identify the epigenetic reader ZMYND8 as a key mediator of TNBC spinal metastasis. ZMYND8 is significantly upregulated in spinal metastatic lesions and correlates with adverse patient outcomes. Transcriptomic profiling reveals that spinal metastases display profoundly immunosuppressive microenvironments, with elevated M2 macrophage infiltration positively associated with ZMYND8 expression. Mechanistically, ZMYND8 functions as a scaffold protein that promotes assembly of the DDX3X–CK1ε complex, thereby activating WNT/β-catenin signaling and promoting spinal metastasis. Furthermore, we identify OTUD4 as a bona fide deubiquitinase that directly interacts with and stabilizes ZMYND8, thereby enhancing TNBC cell migration, invasion, and spinal colonization. The resulting OTUD4–ZMYND8–DDX3X signaling axis drives canonical WNT/β-catenin signaling, upregulates CSF1 expression and promotes M2 polarization of macrophages, collectively fostering invasive behavior and establishing an immunosuppressive niche conducive to spinal metastasis. Collectively, these findings establish the OTUD4–ZMYND8–DDX3X axis as a pivotal regulator of spinal metastasis in TNBC and highlight its potential as a therapeutic target for inhibiting metastatic progression.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101259"},"PeriodicalIF":7.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620904","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 : 2025-11-23DOI: 10.1016/j.neo.2025.101257
Nadeem Bhat , Mohammed Soutto , Zheng Chen , Marwah Al-Mathkour , Silvia Giordano , Mohammed Chwihne , Melanie Genoula , Farah Ballout , Shoumin Zhu , Oliver G McDonald , Wael El-Rifai
Oxaliplatin, a platinum-based anticancer drug, is commonly used to treat gastrointestinal cancers, including gastric cancer. However, resistance to platinum-based therapies often leads to poor clinical outcomes for gastric cancer patients. Overexpression and activation of FGFR4 signaling have been identified as drivers of tumorigenesis in several types of cancer, including gastric cancer. In this study, we investigated the therapeutic efficacy of combining the FGFR4 inhibitor H3B-6527 with oxaliplatin using in vitro and in vivo gastric cancer models. Using gastric cancer cell lines, cell viability and clonogenic cell survival assays revealed that the combination treatment significantly reduced cancer cell viability and colony formation, compared to either agent alone (p < 0.01). Interestingly, treatment with oxaliplatin alone increased FGFR4 expression in the resistant cancer cell population. Western blot analysis confirmed the heightened DNA damage (γH2AX, cleaved PARP) alongside suppressed pro-survival signals (phospho-STAT3 and BCL2 family). Apoptosis was markedly enhanced, as demonstrated by Caspase-3/7 and TUNEL assays (p < 0.01). In human gastric cancer-derived tumoroids, the combination therapy significantly reduced both the size and number of tumoroids. In patient-derived xenograft (PDX) models, the combined treatment approach outperformed single-agent treatments in reducing tumor growth and improving survival. Immunofluorescence and immunohistochemistry analyses of PDX tumors showed an increase in DNA damage (γH2AX) and apoptosis (cleaved caspase-3) along with a reduction in cell proliferation (KI67).
These findings indicate that H3B-6527 enhances gastric cancer sensitivity to oxaliplatin by amplifying DNA damage and disrupting cell survival pathways. This study provides a rationale for clinical trials targeting FGFR4 in gastric cancer.
{"title":"Enhancing the antitumor efficacy using a combination of FGFR4 Inhibitor (H3B-6527) and oxaliplatin in gastric cancer","authors":"Nadeem Bhat , Mohammed Soutto , Zheng Chen , Marwah Al-Mathkour , Silvia Giordano , Mohammed Chwihne , Melanie Genoula , Farah Ballout , Shoumin Zhu , Oliver G McDonald , Wael El-Rifai","doi":"10.1016/j.neo.2025.101257","DOIUrl":"10.1016/j.neo.2025.101257","url":null,"abstract":"<div><div>Oxaliplatin, a platinum-based anticancer drug, is commonly used to treat gastrointestinal cancers, including gastric cancer. However, resistance to platinum-based therapies often leads to poor clinical outcomes for gastric cancer patients. Overexpression and activation of FGFR4 signaling have been identified as drivers of tumorigenesis in several types of cancer, including gastric cancer. In this study, we investigated the therapeutic efficacy of combining the FGFR4 inhibitor H3B-6527 with oxaliplatin using in vitro and in vivo gastric cancer models. Using gastric cancer cell lines, cell viability and clonogenic cell survival assays revealed that the combination treatment significantly reduced cancer cell viability and colony formation, compared to either agent alone (<em>p</em> < 0.01). Interestingly, treatment with oxaliplatin alone increased FGFR4 expression in the resistant cancer cell population. Western blot analysis confirmed the heightened DNA damage (γH2AX, cleaved PARP) alongside suppressed pro-survival signals (phospho-STAT3 and BCL2 family). Apoptosis was markedly enhanced, as demonstrated by Caspase-3/7 and TUNEL assays (<em>p</em> < 0.01). In human gastric cancer-derived tumoroids, the combination therapy significantly reduced both the size and number of tumoroids. In patient-derived xenograft (PDX) models, the combined treatment approach outperformed single-agent treatments in reducing tumor growth and improving survival. Immunofluorescence and immunohistochemistry analyses of PDX tumors showed an increase in DNA damage (γH2AX) and apoptosis (cleaved caspase-3) along with a reduction in cell proliferation (KI67).</div><div>These findings indicate that H3B-6527 enhances gastric cancer sensitivity to oxaliplatin by amplifying DNA damage and disrupting cell survival pathways. This study provides a rationale for clinical trials targeting FGFR4 in gastric cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101257"},"PeriodicalIF":7.7,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145597718","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}
A comprehensive understanding of the mechanisms by which air pollutant exposure drives cancer progression remains incomplete. Particulate matter has been shown to induce genotoxicity and mutagenesis through oxidative stress both in vivo and in vitro. However, its impact on the pulmonary immune microenvironment and its role in modulating anti-tumour immune responses remains poorly characterized.
Here, we report that chronic exposure to diesel exhaust particles (DEPs), a major component of PM2.5, induces an immunosuppressive lung microenvironment that promotes tumour progression in a KRAS-driven lung adenocarcinoma model (KrasLSL-G12D/+-Trp53lox/lox or KP mice). This environment is characterized by the emergence of PMN-MDSC (CD14pos PMNs) that exhibit NET formation and an immunosuppressive gene expression and functional profile. Additionally, we observed increased infiltration of regulatory T cells (Tregs), and upregulation of exhaustion/activation and immunosuppressive markers on T cells, factors that likely contribute to the increased tumour burden and enhanced tumour cell proliferation seen in DEP-exposed KP mice.
Our study reveals how chronic DEP exposure reshapes the lung microenvironment in ways that may impair the ability to mount effective anti-tumour immune responses. These findings highlight the need for stronger public and occupational health policies aimed at reducing air pollution and its associated disease burden.
{"title":"Exposure to diesel particulates induces an immunosuppressive microenvironment that promotes the progression of lung cancer","authors":"Marie-Laure Delhez , Maëlle Bosmans , Lucia Rodriguez Rodriguez , Alison Gillard , Silvia Blacher , Arnaud Blomme , Pierre Close , Bénédicte Machiels , Marie-Julie Nokin , Didier Cataldo","doi":"10.1016/j.neo.2025.101255","DOIUrl":"10.1016/j.neo.2025.101255","url":null,"abstract":"<div><div>A comprehensive understanding of the mechanisms by which air pollutant exposure drives cancer progression remains incomplete. Particulate matter has been shown to induce genotoxicity and mutagenesis through oxidative stress both <em>in vivo</em> and <em>in vitro</em>. However, its impact on the pulmonary immune microenvironment and its role in modulating anti-tumour immune responses remains poorly characterized.</div><div>Here, we report that chronic exposure to diesel exhaust particles (DEPs), a major component of PM2.5, induces an immunosuppressive lung microenvironment that promotes tumour progression in a KRAS-driven lung adenocarcinoma model (<em>Kras<sup>LSL-G12D/+</sup>-Trp53<sup>lox/lox</sup></em> or KP mice). This environment is characterized by the emergence of PMN-MDSC (CD14<sup>pos</sup> PMNs) that exhibit NET formation and an immunosuppressive gene expression and functional profile. Additionally, we observed increased infiltration of regulatory T cells (Tregs), and upregulation of exhaustion/activation and immunosuppressive markers on T cells, factors that likely contribute to the increased tumour burden and enhanced tumour cell proliferation seen in DEP-exposed KP mice.</div><div>Our study reveals how chronic DEP exposure reshapes the lung microenvironment in ways that may impair the ability to mount effective anti-tumour immune responses. These findings highlight the need for stronger public and occupational health policies aimed at reducing air pollution and its associated disease burden.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101255"},"PeriodicalIF":7.7,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576960","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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