Transcription factors play a central role in cancer growth, progression, and metastasis, and contribute to intratumor phenotypic plasticity that enable drug tolerance and cancer relapse. Changes in the regulatory activities of transcription factors in cancer may not always be detected from mutational signatures or differential expression of the transcription factors, as done in traditional analysis. In addition, past studies have focused on the activities of transcription factors in tumor as a whole and thus, have not fully captured the heterogeneity in gene regulation among different cell types within the tumor microenvironment. In this work, through an analysis of the transitions in regulatory network architecture and gene regulation dynamics, we identify the central transcription factors associated with lung adenocarcinoma progression. The gene NR2F1, associated with neurodevelopment and cancer dormancy, emerge as a key transcription factor in the progression of lung adenocarcinoma. We further identify transcription factors that are active in only cancer samples and uncover how changes in gene regulation dynamics influence intratumor heterogeneity. Taken together, our work elucidates the transitions in gene regulatory network during cancer progression, identifies central transcription factors in this process, and reveals the complex regulatory changes cooccurring in different cell types within the tumor microenvironment.
{"title":"Gene regulatory network transitions reveal the central transcription factors in lung adenocarcinoma progression.","authors":"Upasana Ray, Adarsh Singh, Debabrata Samanta, Riddhiman Dhar","doi":"10.1038/s41540-025-00640-9","DOIUrl":"10.1038/s41540-025-00640-9","url":null,"abstract":"<p><p>Transcription factors play a central role in cancer growth, progression, and metastasis, and contribute to intratumor phenotypic plasticity that enable drug tolerance and cancer relapse. Changes in the regulatory activities of transcription factors in cancer may not always be detected from mutational signatures or differential expression of the transcription factors, as done in traditional analysis. In addition, past studies have focused on the activities of transcription factors in tumor as a whole and thus, have not fully captured the heterogeneity in gene regulation among different cell types within the tumor microenvironment. In this work, through an analysis of the transitions in regulatory network architecture and gene regulation dynamics, we identify the central transcription factors associated with lung adenocarcinoma progression. The gene NR2F1, associated with neurodevelopment and cancer dormancy, emerge as a key transcription factor in the progression of lung adenocarcinoma. We further identify transcription factors that are active in only cancer samples and uncover how changes in gene regulation dynamics influence intratumor heterogeneity. Taken together, our work elucidates the transitions in gene regulatory network during cancer progression, identifies central transcription factors in this process, and reveals the complex regulatory changes cooccurring in different cell types within the tumor microenvironment.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"18"},"PeriodicalIF":3.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12873405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-20DOI: 10.1038/s41540-025-00638-3
Zhangli Yuan, Wenqian Yan, Ruoyao Wang, Shanshan Yin, Chongchen Pang, Xinyuan Ren, Wenchang Duan, Mika Torhola, Klaus Förger, Henna Kujanen, Yixin Zhang, Haoyan Chen, Hui Shi, Yuqing Lou, Hao Li, Guang He, Yi Shi
Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy driven by complex genetic and epigenetic aberrations. Circular RNAs (circRNAs), characterized by covalently closed structures and exceptional stability, have emerged as promising diagnostic biomarkers. However, existing circRNA-based predictive models largely depend on differential expression, overlooking the potential impact of higher-order chromatin organization on circRNA formation and function. Here, we propose a machine learning framework that integrates three-dimensional (3D) genome architecture to refine circRNA selection for AML prediction. By mapping 9,565 circRNAs onto a 3D chromatin model reconstructed from Hi-C data, we analyzed their spatial clustering and biological pathway enrichment. Eighteen pathways exhibited significant 3D aggregation of circRNAs, enabling radial stratification based on nuclear localization. Five circRNA panels were designed using complementary strategies combining expression, pathway, and spatial features. Cross-validation and external validation across six machine learning algorithms showed that the panel derived from the fifth radial layer (Panel-3DG-Radius5) achieved the most robust and consistent performance (ROC-AUC > 0.99). Integrating 3D genomic context reduced feature collinearity while enhancing biological interpretability. Overall, our study establishes a 3D genome-informed paradigm for circRNA biomarker discovery, demonstrating that spatial genome organization can substantially improve the precision and robustness of AML predictive modeling.
{"title":"Machine learning prediction for AML based on 3D genome selected circRNA.","authors":"Zhangli Yuan, Wenqian Yan, Ruoyao Wang, Shanshan Yin, Chongchen Pang, Xinyuan Ren, Wenchang Duan, Mika Torhola, Klaus Förger, Henna Kujanen, Yixin Zhang, Haoyan Chen, Hui Shi, Yuqing Lou, Hao Li, Guang He, Yi Shi","doi":"10.1038/s41540-025-00638-3","DOIUrl":"10.1038/s41540-025-00638-3","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy driven by complex genetic and epigenetic aberrations. Circular RNAs (circRNAs), characterized by covalently closed structures and exceptional stability, have emerged as promising diagnostic biomarkers. However, existing circRNA-based predictive models largely depend on differential expression, overlooking the potential impact of higher-order chromatin organization on circRNA formation and function. Here, we propose a machine learning framework that integrates three-dimensional (3D) genome architecture to refine circRNA selection for AML prediction. By mapping 9,565 circRNAs onto a 3D chromatin model reconstructed from Hi-C data, we analyzed their spatial clustering and biological pathway enrichment. Eighteen pathways exhibited significant 3D aggregation of circRNAs, enabling radial stratification based on nuclear localization. Five circRNA panels were designed using complementary strategies combining expression, pathway, and spatial features. Cross-validation and external validation across six machine learning algorithms showed that the panel derived from the fifth radial layer (Panel-3DG-Radius5) achieved the most robust and consistent performance (ROC-AUC > 0.99). Integrating 3D genomic context reduced feature collinearity while enhancing biological interpretability. Overall, our study establishes a 3D genome-informed paradigm for circRNA biomarker discovery, demonstrating that spatial genome organization can substantially improve the precision and robustness of AML predictive modeling.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"16"},"PeriodicalIF":3.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12868704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-17DOI: 10.1038/s41540-026-00649-8
Stefan Loipfinger, Arkajyoti Bhattacharya, Carlos G Urzúa-Traslaviña, Marcel A T M van Vugt, Marco de Bruyn, Rudolf S N Fehrmann
Tumors with high copy number alteration (CNA) burden often respond poorly to immune checkpoint inhibitor therapy. However, how CNAs affect the anti-cancer immune response remains unclear. To address this, we set out to capture the transcriptional effects of CNAs and define a comprehensive landscape of immune-related transcriptional patterns. Hereto, we applied consensus independent component analysis to 294,159 bulk transcriptomic profiles. We demonstrated the predictive power of these patterns for immunotherapy response, their reproducibility across platforms, and their applicability to bulk, single-cell, and spatial transcriptomic data. Our analysis identified both novel inverse and positive associations between high CNA burden and immune-related transcriptional patterns across various cancer types. For example, higher CNA burden correlated with increased immunosuppression, including IL-17-producing cells and regulatory T cells. This resource, along with the classification of these transcriptional patterns as immune-suppressive and immune-stimulatory, may provide insights to improve immunotherapy efficacy in tumors with high CNA burden.
{"title":"Association of copy number alterations with the immune transcriptomic landscape in cancer.","authors":"Stefan Loipfinger, Arkajyoti Bhattacharya, Carlos G Urzúa-Traslaviña, Marcel A T M van Vugt, Marco de Bruyn, Rudolf S N Fehrmann","doi":"10.1038/s41540-026-00649-8","DOIUrl":"https://doi.org/10.1038/s41540-026-00649-8","url":null,"abstract":"<p><p>Tumors with high copy number alteration (CNA) burden often respond poorly to immune checkpoint inhibitor therapy. However, how CNAs affect the anti-cancer immune response remains unclear. To address this, we set out to capture the transcriptional effects of CNAs and define a comprehensive landscape of immune-related transcriptional patterns. Hereto, we applied consensus independent component analysis to 294,159 bulk transcriptomic profiles. We demonstrated the predictive power of these patterns for immunotherapy response, their reproducibility across platforms, and their applicability to bulk, single-cell, and spatial transcriptomic data. Our analysis identified both novel inverse and positive associations between high CNA burden and immune-related transcriptional patterns across various cancer types. For example, higher CNA burden correlated with increased immunosuppression, including IL-17-producing cells and regulatory T cells. This resource, along with the classification of these transcriptional patterns as immune-suppressive and immune-stimulatory, may provide insights to improve immunotherapy efficacy in tumors with high CNA burden.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-16DOI: 10.1038/s41540-026-00647-w
Donggu Lee, Sean Lawler, Yangjin Kim
Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. A connection between asthma and optic glioma has previously been observed, but the mechanisms are unclear. To elucidate the role of asthma in the regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in the regulation of microglia, a key player in the glioma tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that inflammation can play a key role in suppressing the proliferation of optic glioma cells via immune reprogramming of T cells and the delicate control of signaling networks in microglia. Our mathematical model unveils the complex interactions between tumor and immune cells in optic glioma. Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.
{"title":"Asthma-mediated control of optic glioma growth via T cell-microglia interactions: A mathematical model.","authors":"Donggu Lee, Sean Lawler, Yangjin Kim","doi":"10.1038/s41540-026-00647-w","DOIUrl":"https://doi.org/10.1038/s41540-026-00647-w","url":null,"abstract":"<p><p>Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. A connection between asthma and optic glioma has previously been observed, but the mechanisms are unclear. To elucidate the role of asthma in the regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in the regulation of microglia, a key player in the glioma tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that inflammation can play a key role in suppressing the proliferation of optic glioma cells via immune reprogramming of T cells and the delicate control of signaling networks in microglia. Our mathematical model unveils the complex interactions between tumor and immune cells in optic glioma. Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1038/s41540-025-00645-4
Malvina Marku, Hugo Chenel, Julie Bordenave, Marcelo Hurtado, Marcin Domagala, Flavien Raynal, Mary Poupot, Loïc Ysebaert, Andrei Zinovyev, Vera Pancaldi
How do cancer cells respond to their environment, and what are the key regulators behind their behaviour? While immune cell reprogramming in the tumour microenvironment (TME) has been extensively studied, the dynamic regulatory changes within cancer cells in response to interactions with immune cells remain poorly understood. In Chronic Lymphocytic Leukaemia (CLL), this knowledge gap limits our ability to fully grasp the disease progression and to design effective, personalised interventions. To tackle this, we combine time-series transcriptomics with data-driven gene regulatory network (GRN) inference to uncover the temporal regulatory mechanisms driving CLL cell behaviour within a reconstituted in vitro TME. Using cultures of peripheral blood from CLL patients or of purified patient-derived CLL cells, we profile gene expression across five time points spanning 14 days under these experimental conditions. By inferring GRNs from transcription factor activity, we capture patient-specific and temporally resolved regulatory interactions that highlight how immune signals drive cancer cell phenotypic changes. Our network analysis reveals distinct gene modules associated with critical processes such as cytokine signalling, metabolic reprogramming and differentiation, hallmarks of immune-cancer cell interaction. Intriguingly, we found that while the presence of immune cells in the environment significantly alters CLL cell activation, their survival trajectories are predominantly governed by intrinsic features. This study not only offers mechanistic insights into how immune cell presence influences CLL cell fate but also presents a robust computational framework for integrating time-series transcriptomics with GRN inference, which can then be used to study the long-term behaviour of the CLL cells through dynamical modelling.
{"title":"Data driven network inference and longitudinal transcriptomics unveil dynamic regulation in Chronic Lymphocytic Leukaemia models.","authors":"Malvina Marku, Hugo Chenel, Julie Bordenave, Marcelo Hurtado, Marcin Domagala, Flavien Raynal, Mary Poupot, Loïc Ysebaert, Andrei Zinovyev, Vera Pancaldi","doi":"10.1038/s41540-025-00645-4","DOIUrl":"10.1038/s41540-025-00645-4","url":null,"abstract":"<p><p>How do cancer cells respond to their environment, and what are the key regulators behind their behaviour? While immune cell reprogramming in the tumour microenvironment (TME) has been extensively studied, the dynamic regulatory changes within cancer cells in response to interactions with immune cells remain poorly understood. In Chronic Lymphocytic Leukaemia (CLL), this knowledge gap limits our ability to fully grasp the disease progression and to design effective, personalised interventions. To tackle this, we combine time-series transcriptomics with data-driven gene regulatory network (GRN) inference to uncover the temporal regulatory mechanisms driving CLL cell behaviour within a reconstituted in vitro TME. Using cultures of peripheral blood from CLL patients or of purified patient-derived CLL cells, we profile gene expression across five time points spanning 14 days under these experimental conditions. By inferring GRNs from transcription factor activity, we capture patient-specific and temporally resolved regulatory interactions that highlight how immune signals drive cancer cell phenotypic changes. Our network analysis reveals distinct gene modules associated with critical processes such as cytokine signalling, metabolic reprogramming and differentiation, hallmarks of immune-cancer cell interaction. Intriguingly, we found that while the presence of immune cells in the environment significantly alters CLL cell activation, their survival trajectories are predominantly governed by intrinsic features. This study not only offers mechanistic insights into how immune cell presence influences CLL cell fate but also presents a robust computational framework for integrating time-series transcriptomics with GRN inference, which can then be used to study the long-term behaviour of the CLL cells through dynamical modelling.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"24"},"PeriodicalIF":3.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-15DOI: 10.1038/s41540-025-00643-6
Kurt J A Pumares, Daniel P Martins, Aiman Khalil, Jochen H M Prehn, Deirdre Kilbane
Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy. Recent developments in sequencing, proteomics and network analysis tools provide new avenues for investigating potential molecular therapeutic targets. Both the TGF-β/SMAD signaling pathways and subsets of microRNAs (including miR-21a-5p, miR-142a-5p, and miR-10a-5p) have been shown to be altered in several preclinical models of epilepsy and were mathematically modeled in this study. Using prior systems-based findings, a changeover between 'seizure' and 'anti-seizure' cellular states has been identified upon inhibition of microRNA activity achieved by the injection of antagomirs. Methods for seizure suppression were explored under various antagomir dosages as well as the regulatory effect of each microRNA in order to ascertain intracellular responses. Promising antagomir administration strategies were then identified, which may offer new avenues for seizure suppression.
{"title":"Modeling the microRNA regulation of TGF-β/SMAD signaling pathways for seizure control in temporal lobe epilepsy.","authors":"Kurt J A Pumares, Daniel P Martins, Aiman Khalil, Jochen H M Prehn, Deirdre Kilbane","doi":"10.1038/s41540-025-00643-6","DOIUrl":"10.1038/s41540-025-00643-6","url":null,"abstract":"<p><p>Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy. Recent developments in sequencing, proteomics and network analysis tools provide new avenues for investigating potential molecular therapeutic targets. Both the TGF-β/SMAD signaling pathways and subsets of microRNAs (including miR-21a-5p, miR-142a-5p, and miR-10a-5p) have been shown to be altered in several preclinical models of epilepsy and were mathematically modeled in this study. Using prior systems-based findings, a changeover between 'seizure' and 'anti-seizure' cellular states has been identified upon inhibition of microRNA activity achieved by the injection of antagomirs. Methods for seizure suppression were explored under various antagomir dosages as well as the regulatory effect of each microRNA in order to ascertain intracellular responses. Promising antagomir administration strategies were then identified, which may offer new avenues for seizure suppression.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"21"},"PeriodicalIF":3.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12881450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41540-025-00646-3
Yacong Li, Jun Liu, Xiangyun Bai, Qince Li, Dong Sui, Deyan Yang, Lei Ma, Kuanquan Wang, Henggui Zhang
Bio-pacemakers offer a potential alternative to electronic devices, yet their stable implementation at cellular and tissue levels remains unresolved. In this computational study, we aimed to investigate possible effects of the electrotonic interaction between cardiac cells and the spatial distribution of the bio-pacemaker on the initiation and conduction of cardiac pacemaking action potentials to surrounding quiescent cardiac tissues. Simulation results demonstrated that (i) a combination of weak gap junctional electrical coupling among PMs; and (ii) rectified coupling arising from heterotypic gap junction expressions between the PM and ventricle yielded the best stable and robust bio-pacemaker for pacing and driving surrounding ventricular tissue. Furthermore, Isolated or septal placement improved ventricular pacing efficacy. This study adopts a digital health approach, providing an important theoretical foundation for the simulation of new clinical therapies.
{"title":"Mechanisms of rectified gap junctional coupling enhancing pacemaking activity of biologically engineered pacemaker cells.","authors":"Yacong Li, Jun Liu, Xiangyun Bai, Qince Li, Dong Sui, Deyan Yang, Lei Ma, Kuanquan Wang, Henggui Zhang","doi":"10.1038/s41540-025-00646-3","DOIUrl":"10.1038/s41540-025-00646-3","url":null,"abstract":"<p><p>Bio-pacemakers offer a potential alternative to electronic devices, yet their stable implementation at cellular and tissue levels remains unresolved. In this computational study, we aimed to investigate possible effects of the electrotonic interaction between cardiac cells and the spatial distribution of the bio-pacemaker on the initiation and conduction of cardiac pacemaking action potentials to surrounding quiescent cardiac tissues. Simulation results demonstrated that (i) a combination of weak gap junctional electrical coupling among PMs; and (ii) rectified coupling arising from heterotypic gap junction expressions between the PM and ventricle yielded the best stable and robust bio-pacemaker for pacing and driving surrounding ventricular tissue. Furthermore, Isolated or septal placement improved ventricular pacing efficacy. This study adopts a digital health approach, providing an important theoretical foundation for the simulation of new clinical therapies.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"25"},"PeriodicalIF":3.5,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-10DOI: 10.1038/s41540-025-00644-5
Alexander Smith, Rui Pinto, Loukas Zagkos, Ioanna Tzoulaki, Paul Elliott, Abbas Dehghan
Metabolomics data are often generated through different platforms and quantification methods which makes their synthesis and large-scale replication challenging. This study developed an ensemble of importance-weighted autoencoders to perform cross-platform metabolomics imputation between two metabolomics platforms, Metabolon and National Phenome Centre (NPC) at Imperial College, using 979 samples from the Airwave Health Monitoring Study. The generated samples were highly correlated with real values across all metabolites (µρ = 0.61 (0.55-0.67)). The well-imputed subset contained 199 metabolites (22%), capturing ≥ 55% variance (R² ≥ 0.55) with minimal uncertainty (R² variance ≤ 0.025), including 43 metabolites unique to Metabolon. The concordance of associations in 2,971 validation samples between real and imputed metabolites with two clinical outcomes, body mass index (BMI) and C-reactive protein (CRP), were highly correlated (ρBMI = 0.93; ρCRP = 0.89) with minimal mean difference (BMI µΔ = 0.005 (0.04); CRP µΔ = 0.005 (0.04)). Similar concordance occurred with equivalent UK Biobank (BMI µΔ = -0.007 (0.05); CRP µΔ = 0.01 (0.04)) and NPC (BMI µΔ = -0.013 (0.04); CRP µΔ = -0.019 (0.04)) metabolites. This methodological innovation offers a scalable and accurate method for cross-platform imputation, enabling the aggregation of metabolomics data from different epidemiological studies for replication and meta-analyses.
{"title":"Cross-platform metabolomics imputation using importance-weighted autoencoders.","authors":"Alexander Smith, Rui Pinto, Loukas Zagkos, Ioanna Tzoulaki, Paul Elliott, Abbas Dehghan","doi":"10.1038/s41540-025-00644-5","DOIUrl":"10.1038/s41540-025-00644-5","url":null,"abstract":"<p><p>Metabolomics data are often generated through different platforms and quantification methods which makes their synthesis and large-scale replication challenging. This study developed an ensemble of importance-weighted autoencoders to perform cross-platform metabolomics imputation between two metabolomics platforms, Metabolon and National Phenome Centre (NPC) at Imperial College, using 979 samples from the Airwave Health Monitoring Study. The generated samples were highly correlated with real values across all metabolites (µ<sub>ρ</sub> = 0.61 (0.55-0.67)). The well-imputed subset contained 199 metabolites (22%), capturing ≥ 55% variance (R² ≥ 0.55) with minimal uncertainty (R² variance ≤ 0.025), including 43 metabolites unique to Metabolon. The concordance of associations in 2,971 validation samples between real and imputed metabolites with two clinical outcomes, body mass index (BMI) and C-reactive protein (CRP), were highly correlated (ρ<sub>BMI</sub> = 0.93; ρ<sub>CRP</sub> = 0.89) with minimal mean difference (BMI µ<sub>Δ</sub> = 0.005 (0.04); CRP µ<sub>Δ</sub> = 0.005 (0.04)). Similar concordance occurred with equivalent UK Biobank (BMI µ<sub>Δ</sub> = -0.007 (0.05); CRP µ<sub>Δ</sub> = 0.01 (0.04)) and NPC (BMI µ<sub>Δ</sub> = -0.013 (0.04); CRP µ<sub>Δ</sub> = -0.019 (0.04)) metabolites. This methodological innovation offers a scalable and accurate method for cross-platform imputation, enabling the aggregation of metabolomics data from different epidemiological studies for replication and meta-analyses.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"23"},"PeriodicalIF":3.5,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145945278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41540-025-00625-8
Ozan Kahramanoğulları
Chemical reaction networks (CRNs) are broadly used to study biological systems via simulations. Gillespie's Stochastic Simulation Algorithm (SSA) is commonly used to perform stochastic simulations with CRNs. Comparing two CRNs in such a setting relies on ad hoc signals obtained from the time series, which the simulations output by discarding causal patterns. To this end, we introduce a general method and its implementation for quantitatively comparing CRNs' dynamic behaviour based on causal dependencies in stochastic simulations. Our method detects causal patterns, as in Petri nets, as resource dependencies between reactions during simulation. We present our method within a conservative extension of SSA that tracks and logs these dependencies in simulations as weighted directed graphs. These graphs provide discrete structures that quantify the CRNs' stochastic dynamic behaviour, complementing the simulations' time series output. We use these graphs to compare the behaviour of any two CRNs for the resource dependencies of their components for any time interval. We measure the similarity of the two CRNs via a distance metric. We illustrate different use cases of our method on models of various molecular mechanisms, including gene regulation and drug metabolism.
{"title":"Quantifying and comparing causal patterns in stochastic chemical reaction networks.","authors":"Ozan Kahramanoğulları","doi":"10.1038/s41540-025-00625-8","DOIUrl":"10.1038/s41540-025-00625-8","url":null,"abstract":"<p><p>Chemical reaction networks (CRNs) are broadly used to study biological systems via simulations. Gillespie's Stochastic Simulation Algorithm (SSA) is commonly used to perform stochastic simulations with CRNs. Comparing two CRNs in such a setting relies on ad hoc signals obtained from the time series, which the simulations output by discarding causal patterns. To this end, we introduce a general method and its implementation for quantitatively comparing CRNs' dynamic behaviour based on causal dependencies in stochastic simulations. Our method detects causal patterns, as in Petri nets, as resource dependencies between reactions during simulation. We present our method within a conservative extension of SSA that tracks and logs these dependencies in simulations as weighted directed graphs. These graphs provide discrete structures that quantify the CRNs' stochastic dynamic behaviour, complementing the simulations' time series output. We use these graphs to compare the behaviour of any two CRNs for the resource dependencies of their components for any time interval. We measure the similarity of the two CRNs via a distance metric. We illustrate different use cases of our method on models of various molecular mechanisms, including gene regulation and drug metabolism.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":"12 1","pages":"7"},"PeriodicalIF":3.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145934547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41540-025-00635-6
Jana L Gevertz, Harsh Vardhan Jain, Irina Kareva, Kathleen P Wilkie, Joel Brown, Yitong Pepper Huang, Eduardo Sontag, Vladimir Vinogradov, Mark Davies
Cancer therapies often fail when intolerable toxicity or drug-resistant cancer cells undermine otherwise effective treatment strategies. Over the past decade, adaptive therapy has emerged as a promising approach to postpone emergence of resistance by altering dose timing based on tumor burden thresholds. Despite encouraging results, these protocols often overlook the crucial role of toxicity-induced treatment breaks, which may permit tumor regrowth. Herein, we explore the following question: would incorporating toxicity feedback improve or hinder the efficacy of adaptive therapy? To address this question, we propose a mathematical framework for incorporating toxic feedback into treatment design. We find that the degree of competition between sensitive and resistant populations, along with the growth rate of resistant cells, critically modulates the impact of toxicity feedback on time to progression. Further, our conceptual model identifies circumstances where strategic treatment breaks, which may be based on either tumor size or toxicity, can mitigate overtreatment and extend time to progression, both at the baseline parameterization and across a heterogeneous virtual population. Taken together, these findings highlight the importance of integrating toxicity considerations into the design of adaptive therapy.
{"title":"Delaying cancer progression by integrating toxicity constraints in a model of adaptive therapy.","authors":"Jana L Gevertz, Harsh Vardhan Jain, Irina Kareva, Kathleen P Wilkie, Joel Brown, Yitong Pepper Huang, Eduardo Sontag, Vladimir Vinogradov, Mark Davies","doi":"10.1038/s41540-025-00635-6","DOIUrl":"10.1038/s41540-025-00635-6","url":null,"abstract":"<p><p>Cancer therapies often fail when intolerable toxicity or drug-resistant cancer cells undermine otherwise effective treatment strategies. Over the past decade, adaptive therapy has emerged as a promising approach to postpone emergence of resistance by altering dose timing based on tumor burden thresholds. Despite encouraging results, these protocols often overlook the crucial role of toxicity-induced treatment breaks, which may permit tumor regrowth. Herein, we explore the following question: would incorporating toxicity feedback improve or hinder the efficacy of adaptive therapy? To address this question, we propose a mathematical framework for incorporating toxic feedback into treatment design. We find that the degree of competition between sensitive and resistant populations, along with the growth rate of resistant cells, critically modulates the impact of toxicity feedback on time to progression. Further, our conceptual model identifies circumstances where strategic treatment breaks, which may be based on either tumor size or toxicity, can mitigate overtreatment and extend time to progression, both at the baseline parameterization and across a heterogeneous virtual population. Taken together, these findings highlight the importance of integrating toxicity considerations into the design of adaptive therapy.</p>","PeriodicalId":19345,"journal":{"name":"NPJ Systems Biology and Applications","volume":" ","pages":"11"},"PeriodicalIF":3.5,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}