Pub 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":"2026-01-29","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 : 2026-01-28DOI: 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":"2026-01-28","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 : 2026-01-21DOI: 10.1016/j.neo.2025.101268
Anna LK Gonye , Linda Orzolek , Christopher Cherry , Michael Patatanian , Luke V Loftus , Kevin Truskowski , George Butler , Kenneth J Pienta , Sarah R Amend
Chemotherapy resistance remains a critical barrier in cancer treatment, partly driven by polyploid cells that survive therapy and contribute to tumor recurrence. Here, we investigated epigenomic and transcriptional changes associated with cisplatin-surviving polyploid cells compared to parental cancer cells in prostate cancer (PC3) and triple-negative breast cancer (MDA-MB-231) cell lines. We observed persistent dysregulation of chromatin compaction and altered nuclear structure in polyploid cells following cisplatin treatment. Genome-wide chromatin accessibility profiling via ATAC-seq revealed significant remodeling, notably decreased promoter accessibility at proliferation-associated loci and increased accessibility of distal regulatory elements linked to inflammation and stress response. RNA-seq analyses demonstrated a coordinated transcriptional shift away from proliferative signatures toward inflammatory and survival pathways, including activation of NFκB, interferon response, and integrated stress response pathways. Importantly, we identified subsets of genes showing concordant changes in promoter accessibility and transcriptional activity, directly linking chromatin remodeling to transcriptional reprogramming. These integrated findings highlight the role of chromatin dynamics and epigenetic plasticity in chemotherapy resistance, demonstrating that widespread chromatin accessibility changes facilitate the transition to a stress-adapted, polyploid cell state. This study provides new insights into the molecular mechanisms supporting cancer cell persistence after chemotherapy.
{"title":"Polyploid cisplatin-resistant cancer cells have altered nuclear organization and epigenomic status","authors":"Anna LK Gonye , Linda Orzolek , Christopher Cherry , Michael Patatanian , Luke V Loftus , Kevin Truskowski , George Butler , Kenneth J Pienta , Sarah R Amend","doi":"10.1016/j.neo.2025.101268","DOIUrl":"10.1016/j.neo.2025.101268","url":null,"abstract":"<div><div>Chemotherapy resistance remains a critical barrier in cancer treatment, partly driven by polyploid cells that survive therapy and contribute to tumor recurrence. Here, we investigated epigenomic and transcriptional changes associated with cisplatin-surviving polyploid cells compared to parental cancer cells in prostate cancer (PC3) and triple-negative breast cancer (MDA-MB-231) cell lines. We observed persistent dysregulation of chromatin compaction and altered nuclear structure in polyploid cells following cisplatin treatment. Genome-wide chromatin accessibility profiling via ATAC-seq revealed significant remodeling, notably decreased promoter accessibility at proliferation-associated loci and increased accessibility of distal regulatory elements linked to inflammation and stress response. RNA-seq analyses demonstrated a coordinated transcriptional shift away from proliferative signatures toward inflammatory and survival pathways, including activation of NFκB, interferon response, and integrated stress response pathways. Importantly, we identified subsets of genes showing concordant changes in promoter accessibility and transcriptional activity, directly linking chromatin remodeling to transcriptional reprogramming. These integrated findings highlight the role of chromatin dynamics and epigenetic plasticity in chemotherapy resistance, demonstrating that widespread chromatin accessibility changes facilitate the transition to a stress-adapted, polyploid cell state. This study provides new insights into the molecular mechanisms supporting cancer cell persistence after chemotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101268"},"PeriodicalIF":7.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146031359","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 : 2026-01-15DOI: 10.1016/j.neo.2025.101266
Farinaz Barghi , M. Reza Saadatzadeh , Erika A. Dobrota , Harlan E. Shannon , Barbara J. Bailey , Courtney Young , Rada Malko , Ryli Justice , Niknam Riyahi , Christopher Davis , Khadijeh Bijangi-Vishehsaraei , Keiko Kreklau , Lauren K. Stevens , Jenna Koenig , Shirzat Sulayman , Sheng Liu , Jun Wan , Melissa A. Trowbridge , Kathy Coy , Felicia M. Kennedy , Karen E. Pollok
Osteosarcoma (OS) in pediatric, adolescent, and young adult (AYA) patients is an aggressive bone cancer with limited treatment options. Dysregulation of the CDK4/6–cyclin D axis and the PI3K/mTOR pathway contributes to OS pathogenesis, providing a biological rationale for co-targeting these signaling nodes. However, pharmacologic CDK4/6 inhibition can trigger compensatory activation of the PI3K/mTOR pathway, restoring D-type cyclin expression and partially reactivating CDK4/6 signaling. Thus, dual inhibition of the CDK4/6 and PI3K/mTOR pathways not only addresses two parallel oncogenic drivers but may also prevent potential CDK4/6 inhibitor resistance mediated by feedback activation of PI3K/mTOR. In this study, we tested the hypothesis that coordinated targeting of these pathways would improve tumor control in preclinical OS models. In vitro sensitivity analyses using palbociclib and voxtalisib demonstrated additive to synergistic OS growth suppression, with palbociclib inducing G1 arrest and senescence, and the combination enhancing autophagy. Furthermore, the efficacy, tolerability, and mechanisms of palbociclib and voxtalisib, alone or in combination, were evaluated in molecularly defined primary treatment-naïve, and relapsed/metastatic OS models. In the relapsed/metastatic PDX77-TT2 model, short-term palbociclib exposure activated PI3K/mTOR signaling, whereas the combination of palbociclib and voxtalisib in long-term studies produced marked tumor suppression and extended survival. In the primary treatment-naïve PDX96 model, long-term palbociclib exposure generated a robust CDK4/6 pharmacodynamic response. The addition of voxtalisib reinforced autophagy, sustained CDK pathway inhibition, and improved overall tumor control. In an OS lung-colonization model, CDK4/6 inhibition alone markedly reduced OS lung nodules, with combination therapy providing comparable suppression. Dual CDK4/6–PI3K/mTOR inhibition achieves tumor control across various OS models, supporting the use of genomically guided, pathway-targeted strategies for pediatric and AYA OS.
{"title":"Dual CDK4/6–PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma","authors":"Farinaz Barghi , M. Reza Saadatzadeh , Erika A. Dobrota , Harlan E. Shannon , Barbara J. Bailey , Courtney Young , Rada Malko , Ryli Justice , Niknam Riyahi , Christopher Davis , Khadijeh Bijangi-Vishehsaraei , Keiko Kreklau , Lauren K. Stevens , Jenna Koenig , Shirzat Sulayman , Sheng Liu , Jun Wan , Melissa A. Trowbridge , Kathy Coy , Felicia M. Kennedy , Karen E. Pollok","doi":"10.1016/j.neo.2025.101266","DOIUrl":"10.1016/j.neo.2025.101266","url":null,"abstract":"<div><div>Osteosarcoma (OS) in pediatric, adolescent, and young adult (AYA) patients is an aggressive bone cancer with limited treatment options. Dysregulation of the CDK4/6–cyclin D axis and the PI3K/mTOR pathway contributes to OS pathogenesis, providing a biological rationale for co-targeting these signaling nodes. However, pharmacologic CDK4/6 inhibition can trigger compensatory activation of the PI3K/mTOR pathway, restoring <span>D</span>-type cyclin expression and partially reactivating CDK4/6 signaling. Thus, dual inhibition of the CDK4/6 and PI3K/mTOR pathways not only addresses two parallel oncogenic drivers but may also prevent potential CDK4/6 inhibitor resistance mediated by feedback activation of PI3K/mTOR. In this study, we tested the hypothesis that coordinated targeting of these pathways would improve tumor control in preclinical OS models. In vitro sensitivity analyses using palbociclib and voxtalisib demonstrated additive to synergistic OS growth suppression, with palbociclib inducing G1 arrest and senescence, and the combination enhancing autophagy. Furthermore, the efficacy, tolerability, and mechanisms of palbociclib and voxtalisib, alone or in combination, were evaluated in molecularly defined primary treatment-naïve, and relapsed/metastatic OS models. In the relapsed/metastatic PDX77-TT2 model, short-term palbociclib exposure activated PI3K/mTOR signaling, whereas the combination of palbociclib and voxtalisib in long-term studies produced marked tumor suppression and extended survival. In the primary treatment-naïve PDX96 model, long-term palbociclib exposure generated a robust CDK4/6 pharmacodynamic response. The addition of voxtalisib reinforced autophagy, sustained CDK pathway inhibition, and improved overall tumor control. In an OS lung-colonization model, CDK4/6 inhibition alone markedly reduced OS lung nodules, with combination therapy providing comparable suppression. Dual CDK4/6–PI3K/mTOR inhibition achieves tumor control across various OS models, supporting the use of genomically guided, pathway-targeted strategies for pediatric and AYA OS.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101266"},"PeriodicalIF":7.7,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977344","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 : 2026-01-13DOI: 10.1016/j.neo.2026.101272
Xiaokang Zhang , Bjarne Johannessen , Susanne G. Kidd , Mari Bogaard , Ane Stranger , Ulrika Axcrona , Karol Axcrona , Rolf I. Skotheim
Prostate cancer, among the most prevalent cancer types globally, exhibits marked heterogeneity and varying disease progression and clinical outcomes. Improved molecular subtyping is needed for patient stratification. Since prostate cancer has relatively few somatic point mutations, whole-transcriptome data instead offers a rich and relevant source of molecular data. We analyzed bulk tissue transcriptomes from four cohorts to characterize primary prostate cancer’s cell type composition. A deconvolution of cell types was performed based on gene expression profiles. Patients with available multi-sample regional data from different tumor foci were analyzed for intrapatient heterogeneity. Three cell type composition subtypes were defined: T cells enriched (TCE), epithelial cells enriched (EPCE), and tumor-associated stromal cells enriched (TASCE). A machine learning model was developed to classify these subtypes and validated in three independent cohorts. The subtyping demonstrated a high correlation with established clinicopathological parameters (e.g., Gleason score, p-value < 0.05), and the classifier showed a promising ability to predict biochemical recurrence. Moreover, our analysis revealed that interfocal heterogeneity in patients with multifocal cancer significantly surpassed intrafocal heterogeneity (p-value < 0.05). In conclusion, this study provides a novel prostate cancer subgrouping based on cell type composition, with the TASCE subtype significantly associated with high biochemical recurrence risk.
{"title":"Cell type composition in bulk prostate cancer tissue is a prognostic biomarker","authors":"Xiaokang Zhang , Bjarne Johannessen , Susanne G. Kidd , Mari Bogaard , Ane Stranger , Ulrika Axcrona , Karol Axcrona , Rolf I. Skotheim","doi":"10.1016/j.neo.2026.101272","DOIUrl":"10.1016/j.neo.2026.101272","url":null,"abstract":"<div><div>Prostate cancer, among the most prevalent cancer types globally, exhibits marked heterogeneity and varying disease progression and clinical outcomes. Improved molecular subtyping is needed for patient stratification. Since prostate cancer has relatively few somatic point mutations, whole-transcriptome data instead offers a rich and relevant source of molecular data. We analyzed bulk tissue transcriptomes from four cohorts to characterize primary prostate cancer’s cell type composition. A deconvolution of cell types was performed based on gene expression profiles. Patients with available multi-sample regional data from different tumor foci were analyzed for intrapatient heterogeneity. Three cell type composition subtypes were defined: T cells enriched (TCE), epithelial cells enriched (EPCE), and tumor-associated stromal cells enriched (TASCE). A machine learning model was developed to classify these subtypes and validated in three independent cohorts. The subtyping demonstrated a high correlation with established clinicopathological parameters (e.g., Gleason score, p-value < 0.05), and the classifier showed a promising ability to predict biochemical recurrence. Moreover, our analysis revealed that interfocal heterogeneity in patients with multifocal cancer significantly surpassed intrafocal heterogeneity (p-value < 0.05). In conclusion, this study provides a novel prostate cancer subgrouping based on cell type composition, with the TASCE subtype significantly associated with high biochemical recurrence risk.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101272"},"PeriodicalIF":7.7,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977343","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 : 2026-01-06DOI: 10.1016/j.neo.2025.101271
Shreya Budhiraja , Umme H. Faisal , Shivani Baisiwala , Rafal Chojak , Lara Koutah , Noah B. Drewes , Sia Cho , Hasaan A Kazi , Rebecca Chen , Ella N Perrault , Li Chen , Cheol H. Park , Maeve C. O’Shea , Khizar Nandoliya , Joseph T. Duffy , Peiyu Lin , Adam M Sonabend , Crismita C. Dmello , Atique U. Ahmed
Glioblastoma (GBM), the most common and aggressive primary malignant brain tumor in adults, has a median survival of 14.6 months. To identify drivers of GBM pathogenesis, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous neural stem cells bolstered transformation capacity, decreasing survival and causing tumor engraftment in vivo (p<0.01). Further investigation revealed THOC1′s interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. RNA-sequencing analysis revealed that THOC1’s role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 is a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.
STATEMENT OF SIGNIFICANCE
Glioblastoma, the most aggressive malignant brain tumor in adults, relies on a delicate R-loop landscape to promote cell replication while avoiding DNA damage. Targeting THOC1 represents a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.
{"title":"THOC1 complexes with SIN3A to regulate R-loops and promote glioblastoma progression","authors":"Shreya Budhiraja , Umme H. Faisal , Shivani Baisiwala , Rafal Chojak , Lara Koutah , Noah B. Drewes , Sia Cho , Hasaan A Kazi , Rebecca Chen , Ella N Perrault , Li Chen , Cheol H. Park , Maeve C. O’Shea , Khizar Nandoliya , Joseph T. Duffy , Peiyu Lin , Adam M Sonabend , Crismita C. Dmello , Atique U. Ahmed","doi":"10.1016/j.neo.2025.101271","DOIUrl":"10.1016/j.neo.2025.101271","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most common and aggressive primary malignant brain tumor in adults, has a median survival of 14.6 months. To identify drivers of GBM pathogenesis, we conducted a CRISPR-knockout screen, which revealed THO Complex 1 (THOC1) as a key driver. Knocking down THOC1 significantly reduced GBM cell viability across patient-derived xenograft (PDX) lines, enhancing survival (p<0.01) in primary PDX models. Conversely, overexpressing THOC1 in non-cancerous neural stem cells bolstered transformation capacity, decreasing survival and causing tumor engraftment <em>in vivo</em> (p<0.01). Further investigation revealed THOC1′s interaction with SIN3A, a histone deacetylase complex. Histone deacetylation has been previously shown to prevent the buildup of R-loops, structures that form normally during transcription but can be lethal in excess. We found that THOC1-knockdown leads to elevated R-loop levels and reduced histone deacetylation levels. RNA-sequencing analysis revealed that THOC1’s role in R-loop prevention primarily affects telomeres, critical regions for cell replication. We further show that THOC1-knockdown results in significantly increased telomeric R-loop levels and shortened telomeres. Ultimately, this study suggests that targeting THOC1 is a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.</div></div><div><h3>STATEMENT OF SIGNIFICANCE</h3><div>Glioblastoma, the most aggressive malignant brain tumor in adults, relies on a delicate R-loop landscape to promote cell replication while avoiding DNA damage. Targeting THOC1 represents a promising therapeutic strategy to disrupt the delicate R-loop landscape and undermine GBM's replicative potential.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101271"},"PeriodicalIF":7.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913716","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 : 2026-01-06DOI: 10.1016/j.neo.2025.101265
Xianliang Wang , Rengcheng Qian , Zhenlang Lin , Yiying Wang
Background
Bone tumors are rare but highly aggressive malignancies associated with considerable mortality. Emerging evidence identifies obesity as a contributor to multiple malignancies, including those of osseous origin, primarily through mechanisms involving endocrine imbalance and chronic inflammation. Conventional obesity metrics, like body mass index (BMI), cannot reflect the full spectrum of obesity-related risks. In contrast, the age-adjusted visceral adiposity index (AVAI) offers a more holistic evaluation of obesity-associated hazards.
Methods
This cross-sectional analysis utilized National Health and Nutrition Examination Survey (NHANES) data collected between 2011 and 2018. After excluding participants younger than 18 years and those lacking complete information on bone tumors or AVAI, the final analytic cohort comprised 3,731 adults. The AVAI was calculated using BMI, waist circumference, age, high-density lipoprotein levels, and triglyceride levels. The presence of a bone tumor was ascertained through medical questionnaires. Logistic regression analyses were applied to evaluate the association between AVAI levels and the occurrence of bone neoplasms, after adjusting for potential confounders such as hypertension, diabetes, and other metabolic variables.
Results
The prevalence of bone tumors increased with higher AVAI quartiles, reaching 4.07 % in the highest quartile (Q4). Univariate logistic regression demonstrated a significant positive association between AVAI and bone tumors (OR = 1.19, 95 % CI: 1.02–1.31, P < 0.0001). After accounting for all demographic, metabolic, and clinical covariates, higher AVAI quartiles remained strongly associated with elevated bone tumor risk, with adjusted odds ratios of 1.64 (Q2), 2.15 (Q3), and 2.81 (Q4) compared to the reference quartile (Q1).
Conclusion
The findings indicate a significant association between AVAI and the likelihood of bone tumor development, thus emphasizing the necessity of incorporating visceral adiposity into the assessment of skeletal neoplasm incidence. Future studies should focus on the underlying mechanisms and investigate potential interventions targeting obesity-related factors to mitigate the risk of bone tumors.
{"title":"Visceral adiposity as a metabolic risk factor for bone tumors: Insights from the NHANES population-based study","authors":"Xianliang Wang , Rengcheng Qian , Zhenlang Lin , Yiying Wang","doi":"10.1016/j.neo.2025.101265","DOIUrl":"10.1016/j.neo.2025.101265","url":null,"abstract":"<div><h3>Background</h3><div>Bone tumors are rare but highly aggressive malignancies associated with considerable mortality. Emerging evidence identifies obesity as a contributor to multiple malignancies, including those of osseous origin, primarily through mechanisms involving endocrine imbalance and chronic inflammation. Conventional obesity metrics, like body mass index (BMI), cannot reflect the full spectrum of obesity-related risks. In contrast, the age-adjusted visceral adiposity index (AVAI) offers a more holistic evaluation of obesity-associated hazards.</div></div><div><h3>Methods</h3><div>This cross-sectional analysis utilized National Health and Nutrition Examination Survey (NHANES) data collected between 2011 and 2018. After excluding participants younger than 18 years and those lacking complete information on bone tumors or AVAI, the final analytic cohort comprised 3,731 adults. The AVAI was calculated using BMI, waist circumference, age, high-density lipoprotein levels, and triglyceride levels. The presence of a bone tumor was ascertained through medical questionnaires. Logistic regression analyses were applied to evaluate the association between AVAI levels and the occurrence of bone neoplasms, after adjusting for potential confounders such as hypertension, diabetes, and other metabolic variables.</div></div><div><h3>Results</h3><div>The prevalence of bone tumors increased with higher AVAI quartiles, reaching 4.07 % in the highest quartile (Q4). Univariate logistic regression demonstrated a significant positive association between AVAI and bone tumors (OR = 1.19, 95 % CI: 1.02–1.31, <em>P</em> < 0.0001). After accounting for all demographic, metabolic, and clinical covariates, higher AVAI quartiles remained strongly associated with elevated bone tumor risk, with adjusted odds ratios of 1.64 (Q2), 2.15 (Q3), and 2.81 (Q4) compared to the reference quartile (Q1).</div></div><div><h3>Conclusion</h3><div>The findings indicate a significant association between AVAI and the likelihood of bone tumor development, thus emphasizing the necessity of incorporating visceral adiposity into the assessment of skeletal neoplasm incidence. Future studies should focus on the underlying mechanisms and investigate potential interventions targeting obesity-related factors to mitigate the risk of bone tumors.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"72 ","pages":"Article 101265"},"PeriodicalIF":7.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145913719","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 : 2026-01-06DOI: 10.1016/j.neo.2025.101269
Li-Zhu Liao , Chang-Jiun Wu , Yu-An Chen , Tzu-Chin Lin , Po-Hung Lin , Chia-Lin Wei , Kou-Juey Wu
Extrachromosomal DNAs (ecDNAs) play an important role in tumor progression. ecDNA hubs have been shown to be anchored by BRD4, a chromatin reader. However, the chromatin organization of ecDNA hub remains unknown. Here we show that histone 3 lysine 56 acetylation (H3K56ac) mark binds to BRD4 specifically. Knockdown of BRD4 decreased the ecDNA hub signals by the ecTag method. Knockdown of an epigenetic player (USP7), histone acetyltransferase (CBP), or histone chaperone (Asf1a) that regulates H3K56ac mark also decreased ecDNA hub signals and H3K56ac levels, supporting the role of H3K56ac in regulating ecDNA hub maintenance. Co-immunoprecipitation experiments showed the interactions of BRD4, USP7, Asf1a, and CBP. Analysis of ChIP-seq datasets showed that both H3K56ac and H3K27ac converged with BRD4 binding at the ecDNA-chromosome interaction sites and ecDNA itself. However, H3K56ac had a widespread enrichment with most BRD4-occupied sites compared with H3K27ac that occupied a limited subset of BRD4 peaks. These results present a framework of ecDNA hub chromatin organization that maintains ecDNA hub integrity, further providing therapeutic options that could be used to target ecDNA hubs.
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