{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:47:34Z","timestamp":1791323254456,"version":"4.3.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL178032"],"award-info":[{"award-number":["R01HL178032"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL157879"],"award-info":[{"award-number":["R01HL157879"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL127349"],"award-info":[{"award-number":["R01HL127349"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01AA028436"],"award-info":[{"award-number":["R01AA028436"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL089897"],"award-info":[{"award-number":["U01HL089897"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["U01HL089856"],"award-info":[{"award-number":["U01HL089856"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA272218"],"award-info":[{"award-number":["P50CA272218"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA047904"],"award-info":[{"award-number":["P30CA047904"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM150509"],"award-info":[{"award-number":["R35GM150509"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Syst Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gene expression programs that establish and maintain specific cellular states are orchestrated through a regulatory network composed of transcription factors, cofactors, and chromatin regulators. Dysregulation of this network can lead to a broad range of diseases by altering gene programs. This article presents LaGrACE, a novel method designed to estimate dysregulation of gene programs combining omics data with clinical information. This approach facilitates the grouping of samples exhibiting similar patterns of gene program dysregulation, thereby enhancing the discovery of underlying molecular mechanisms in disease subpopulations. We rigorously evaluated LaGrACE\u2019s performance using synthetic data, bulk RNA-seq clinical datasets (breast cancer, chronic obstructive pulmonary disease (COPD)), and single-cell RNA-seq drug perturbation datasets. Our findings demonstrate that LaGrACE is exceptionally robust in identifying biologically meaningful and prognostic molecular subtypes. In addition, it effectively discerns drug response signals at a single-cell resolution. Moreover, the COPD analysis uncovered a new role of LEF1 regulator in COPD molecular mechanisms associated with mortality. Collectively, these results underscore the utility of LaGrACE as a valuable tool for elucidating the underlying mechanisms of diseases.<\/jats:p>","DOI":"10.1038\/s44320-025-00115-3","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T06:59:55Z","timestamp":1751266795000},"page":"1263-1281","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["LaGrACE: estimating gene program dysregulation with latent regulatory network"],"prefix":"10.1038","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9305-1218","authenticated-orcid":false,"given":"Minxue","family":"Jia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyi","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengli","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chih","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3172-3132","authenticated-orcid":false,"given":"Panayiotis V","family":"Benos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"115_CR1","doi-asserted-by":"publisher","unstructured":"Adams TS, Schupp JC, Poli S, Ayaub EA, Neumark N, Ahangari F, Chu SG et al (2020) Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.aba1983","DOI":"10.1126\/sciadv.aba1983"},{"key":"115_CR2","first-page":"4","volume":"104","author":"B Andrews","year":"2019","unstructured":"Andrews B, Ramsey J, Cooper GF (2019) Learning high-dimensional directed acyclic graphs with mixed data-types. Proc Mach Learn Res 104:4\u201321","journal-title":"Proc Mach Learn Res"},{"issue":"1","key":"115_CR3","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.resinv.2021.09.003","volume":"60","author":"J Araya","year":"2022","unstructured":"Araya J, Kuwano K (2022) Cellular senescence\u2014an aging hallmark in chronic obstructive pulmonary disease pathogenesis. Respir Investig 60(1):33\u201344. https:\/\/doi.org\/10.1016\/j.resinv.2021.09.003","journal-title":"Respir Investig"},{"issue":"1","key":"115_CR4","doi-asserted-by":"publisher","DOI":"10.1093\/bioadv\/vbac016","volume":"2","author":"P Badia-i-Mompel","year":"2022","unstructured":"Badia-i-Mompel P, V\u00e9lez Santiago J, Braunger J, Geiss C, Dimitrov D, M\u00fcller-Dott S, Taus P et al (2022) DecoupleR: ensemble of computational methods to infer biological activities from Omics data. Bioinforma Adv 2(1):vbac016. https:\/\/doi.org\/10.1093\/bioadv\/vbac016","journal-title":"Bioinforma Adv"},{"issue":"7269","key":"115_CR5","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature08460","volume":"462","author":"DA Barbie","year":"2009","unstructured":"Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, Schinzel AC et al (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108\u2013112. https:\/\/doi.org\/10.1038\/nature08460","journal-title":"Nature"},{"issue":"4","key":"115_CR6","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1158\/0008-5472.CAN-21-0373","volume":"82","author":"H Beetham","year":"2022","unstructured":"Beetham H, Griffith BGC, Murina O, Loftus AEP, Parry DA, Temps C, Culley J et al (2022) Loss of integrin-linked kinase sensitizes breast cancer to SRC inhibitors. Cancer Res 82(4):632\u2013647. https:\/\/doi.org\/10.1158\/0008-5472.CAN-21-0373","journal-title":"Cancer Res"},{"key":"115_CR7","doi-asserted-by":"publisher","unstructured":"Bernard PS, Parker JS, Mullins M, Cheung MCU, Leung S, Voduc D, Vickery T et al (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. https:\/\/doi.org\/10.1200\/JCO.2008.18.1370.","DOI":"10.1200\/JCO.2008.18.1370"},{"key":"115_CR8","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.isci.2019.03.018","volume":"14","author":"X Bing","year":"2019","unstructured":"Bing X, Bunea F, Royer M, Das J (2019) Latent model-based clustering for biological discovery. IScience 14:125\u2013135. https:\/\/doi.org\/10.1016\/j.isci.2019.03.018","journal-title":"IScience"},{"issue":"12","key":"115_CR9","doi-asserted-by":"publisher","first-page":"4164","DOI":"10.1073\/pnas.0308531101","volume":"101","author":"J-P Brunet","year":"2004","unstructured":"Brunet J-P, Tamayo P, Golub TR, Mesirov JP (2004) Metagenes and molecular pattern discovery using matrix factorization. Proc Natl Acad Sci USA 101(12):4164\u20134169. https:\/\/doi.org\/10.1073\/pnas.0308531101","journal-title":"Proc Natl Acad Sci USA"},{"key":"115_CR10","doi-asserted-by":"publisher","unstructured":"Cadigan KM, Waterman ML (2012) TCF\/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol. https:\/\/doi.org\/10.1101\/cshperspect.a007906.","DOI":"10.1101\/cshperspect.a007906"},{"issue":"6409","key":"115_CR11","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1126\/science.aau0730","volume":"361","author":"J Cao","year":"2018","unstructured":"Cao J, Cusanovich DA, Ramani V, Aghamirzaie D, Pliner HA, Hill AJ, Daza RM et al (2018) Joint profiling of chromatin accessibility and gene expression in thousands of single cells. Science 361(6409):1380\u20131385. https:\/\/doi.org\/10.1126\/science.aau0730","journal-title":"Science"},{"issue":"24","key":"115_CR12","doi-asserted-by":"publisher","first-page":"7296","DOI":"10.1039\/c9an01358j","volume":"144","author":"Y-C Chen","year":"2019","unstructured":"Chen Y-C, Sahoo S, Brien R, Jung S, Humphries B, Lee W, Cheng Y-H et al (2019) Single-cell RNA-sequencing of migratory breast cancer cells: discovering genes associated with cancer metastasis. Analyst 144(24):7296\u20137309. https:\/\/doi.org\/10.1039\/c9an01358j","journal-title":"Analyst"},{"issue":"2","key":"115_CR13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/s41587-021-01033-z","volume":"40","author":"E Dann","year":"2022","unstructured":"Dann E, Henderson NC, Teichmann SA, Morgan MD, Marioni JC (2022) Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat Biotechnol 40(2):245\u2013253. https:\/\/doi.org\/10.1038\/s41587-021-01033-z","journal-title":"Nat Biotechnol"},{"issue":"16","key":"115_CR14","doi-asserted-by":"publisher","first-page":"6388","DOI":"10.1073\/pnas.1219651110","volume":"110","author":"Y Drier","year":"2013","unstructured":"Drier Y, Sheffer M, Domany E (2013) Pathway-based personalized analysis of cancer. Proc Natl Acad Sci USA 110(16):6388\u20136393. https:\/\/doi.org\/10.1073\/pnas.1219651110","journal-title":"Proc Natl Acad Sci USA"},{"key":"115_CR15","doi-asserted-by":"publisher","unstructured":"Elyahu Y, Hekselman I, Eizenberg-Magar I, Berner O, Strominger I, Schiller M, Mittal K et al (2019) Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.aaw8330.","DOI":"10.1126\/sciadv.aaw8330"},{"issue":"4","key":"115_CR16","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1038\/s41375-019-0635-1","volume":"34","author":"K Feder","year":"2020","unstructured":"Feder K, Edmaier-Schr\u00f6ger K, Rawat VPS, Kirsten N, Metzeler K, Kraus JM, D\u00f6hner K et al (2020) Differences in expression and function of LEF1 isoforms in normal versus leukemic hematopoiesis. Leukemia 34(4):1027\u20131037. https:\/\/doi.org\/10.1038\/s41375-019-0635-1","journal-title":"Leukemia"},{"issue":"2","key":"115_CR17","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1136\/thoraxjnl-2020-216401","volume":"77","author":"AJ Ghosh","year":"2022","unstructured":"Ghosh AJ, Saferali A, Lee S, Chase R, Moll M, Morrow J, Yun J, Castaldi PJ, Hersh CP (2022) Blood RNA sequencing shows overlapping gene expression across COPD phenotype domains. Thorax 77(2):115\u2013122. https:\/\/doi.org\/10.1136\/thoraxjnl-2020-216401","journal-title":"Thorax"},{"issue":"9","key":"115_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2020.183278","volume":"1862","author":"L Gonz\u00e1lez-Mariscal","year":"2020","unstructured":"Gonz\u00e1lez-Mariscal L, Miranda J, Gallego-Guti\u00e9rrez H, Cano-Cortina M, Amaya E (2020) Relationship between apical junction proteins, gene expression and cancer. Biochim et Biophys Acta (BBA) - Biomembranes 1862(9):183278. https:\/\/doi.org\/10.1016\/j.bbamem.2020.183278","journal-title":"Biochim et Biophys Acta (BBA) - Biomembranes"},{"issue":"3","key":"115_CR19","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1165\/rcmb.4710","volume":"27","author":"AK Greenberg","year":"2002","unstructured":"Greenberg AK, Hu J, Basu S, Hay J, Reibman J, Yie T-an, Tchou-Wong KM, Rom WN, Lee TC (2002) Glucocorticoids inhibit lung cancer cell growth through both the extracellular signal-related kinase pathway and cell cycle regulators. Am J Respir Cell Mol Biol 27(3):320\u2013328. https:\/\/doi.org\/10.1165\/rcmb.4710","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"18","key":"115_CR20","doi-asserted-by":"publisher","first-page":"4637","DOI":"10.3390\/cancers15184637","volume":"15","author":"X Han","year":"2023","unstructured":"Han X, Han B, Luo H, Ling H, Hu X (2023) Integrated multi-omics profiling of young breast cancer patients reveals a correlation between galactose metabolism pathway and poor disease-free survival. Cancers 15(18):4637. https:\/\/doi.org\/10.3390\/cancers15184637","journal-title":"Cancers"},{"issue":"13","key":"115_CR21","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","volume":"184","author":"Y Hao","year":"2021","unstructured":"Hao Y, Hao S, Andersen-Nissen E, Mauck WM, Zheng S, Butler A, Lee MJ et al (2021) Integrated analysis of multimodal single-cell data. Cell 184(13):3573\u20133587.e29. https:\/\/doi.org\/10.1016\/j.cell.2021.04.048","journal-title":"Cell"},{"issue":"7","key":"115_CR22","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/j.cels.2021.04.010","volume":"12","author":"BD Harris","year":"2021","unstructured":"Harris BD, Crow M, Fischer S, Gillis J (2021) Single-cell co-expression analysis reveals that transcriptional modules are shared across cell types in the brain. Cell Syst 12(7):748\u2013756.e3. https:\/\/doi.org\/10.1016\/j.cels.2021.04.010","journal-title":"Cell Syst"},{"issue":"2","key":"115_CR23","first-page":"236","volume":"79","author":"LD Hill","year":"1993","unstructured":"Hill LD, Sun L, Leuschen MP, Zach TL (1993) C3 synthesis by A549 alveolar epithelial cells is increased by interferon-gamma and dexamethasone. Immunology 79(2):236\u2013240","journal-title":"Immunology"},{"issue":"5a","key":"115_CR24","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1111\/j.1582-4934.2008.00300.x","volume":"12","author":"CV Hinton","year":"2008","unstructured":"Hinton CV, Avraham S, Avraham HK (2008) Contributions of integrin\u2010linked kinase to breast cancer metastasis and tumourigenesis. J Cell Mol Med 12(5a):1517\u20131526. https:\/\/doi.org\/10.1111\/j.1582-4934.2008.00300.x","journal-title":"J Cell Mol Med"},{"issue":"3","key":"115_CR25","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1242\/jcs.03363","volume":"120","author":"S Hoppler","year":"2007","unstructured":"Hoppler S, Kavanagh CL (2007) Wnt signalling: variety at the core. J Cell Sci 120(3):385\u2013393. https:\/\/doi.org\/10.1242\/jcs.03363","journal-title":"J Cell Sci"},{"issue":"10","key":"115_CR26","doi-asserted-by":"publisher","first-page":"2167","DOI":"10.3390\/cells9102167","volume":"9","author":"B Humphries","year":"2020","unstructured":"Humphries B, Wang Z, Yang C (2020) Rho GTPases: big players in breast cancer initiation, metastasis and therapeutic responses. Cells 9(10):2167. https:\/\/doi.org\/10.3390\/cells9102167","journal-title":"Cells"},{"issue":"10","key":"115_CR27","doi-asserted-by":"publisher","first-page":"1467","DOI":"10.1038\/s41587-022-01288-0","volume":"40","author":"L Jerby-Arnon","year":"2022","unstructured":"Jerby-Arnon L, Regev A (2022) DIALOGUE maps multicellular programs in tissue from single-cell or spatial transcriptomics data. Nat Biotechnol 40(10):1467\u20131477. https:\/\/doi.org\/10.1038\/s41587-022-01288-0","journal-title":"Nat Biotechnol"},{"key":"115_CR28","doi-asserted-by":"publisher","unstructured":"Jia M, Sayed K, Kapetanaki MG, Dion W, Rosas L, Irfan S, Valenzi E et al (2023) LEF1 isoforms regulate cellular senescence and aging. Aging Cell 22 (12). https:\/\/doi.org\/10.1111\/acel.14024","DOI":"10.1111\/acel.14024"},{"issue":"37","key":"115_CR29","doi-asserted-by":"publisher","first-page":"4829","DOI":"10.1038\/onc.2016.32","volume":"35","author":"J Johnson","year":"2016","unstructured":"Johnson J, Thijssen B, McDermott U, Garnett M, Wessels LFA, Bernards R (2016) Targeting the RB-E2F pathway in breast cancer. Oncogene 35(37):4829\u20134835. https:\/\/doi.org\/10.1038\/onc.2016.32","journal-title":"Oncogene"},{"issue":"1","key":"115_CR30","doi-asserted-by":"publisher","first-page":"221","DOI":"10.18388\/abp.2001_5129","volume":"48","author":"A Kobielak","year":"2001","unstructured":"Kobielak A, Kobielak K, Trzeciak WH (2001) A novel isoform of human lymphoid enhancer-binding factor-1 (LEF-1) gene transcript encodes a protein devoid of HMG domain and nuclear localization signal. Acta Biochim Polonica 48(1):221\u2013226","journal-title":"Acta Biochim Polonica"},{"key":"115_CR31","doi-asserted-by":"publisher","unstructured":"Kotliar D, Veres A, Nagy MA, Tabrizi S, Hodis E, Melton DA, Sabeti PC (2019) Identifying gene expression programs of cell-type identity and cellular activity with single-cell RNA-seq. eLife. https:\/\/doi.org\/10.7554\/eLife.43803","DOI":"10.7554\/eLife.43803"},{"key":"115_CR32","doi-asserted-by":"publisher","unstructured":"Kunes RZ, Walle T, Land M, Nawy T, Pe\u2019er D (2023) Supervised discovery of interpretable gene programs from single-cell data. Nat Biotechnol. https:\/\/doi.org\/10.1038\/s41587-023-01940-3","DOI":"10.1038\/s41587-023-01940-3"},{"issue":"4","key":"115_CR33","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.cell.2018.01.029","volume":"172","author":"SA Lambert","year":"2018","unstructured":"Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, Chen X, Taipale J, Hughes TR, Weirauch MT (2018) The human transcription factors. Cell 172(4):650\u2013665. https:\/\/doi.org\/10.1016\/j.cell.2018.01.029","journal-title":"Cell"},{"issue":"1","key":"115_CR34","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1080\/10618600.2014.900500","volume":"24","author":"JD Lee","year":"2015","unstructured":"Lee JD, Hastie TJ (2015) Learning the structure of mixed graphical models. J Comput Graph Stat 24(1):230\u2013253. https:\/\/doi.org\/10.1080\/10618600.2014.900500","journal-title":"J Comput Graph Stat"},{"issue":"6","key":"115_CR35","doi-asserted-by":"publisher","first-page":"1237","DOI":"10.1016\/j.cell.2013.02.014","volume":"152","author":"TI Lee","year":"2013","unstructured":"Lee TI, Young RA (2013) Transcriptional regulation and its misregulation in disease. Cell 152(6):1237\u20131251. https:\/\/doi.org\/10.1016\/j.cell.2013.02.014","journal-title":"Cell"},{"issue":"12","key":"115_CR36","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1038\/s41592-018-0229-2","volume":"15","author":"R Lopez","year":"2018","unstructured":"Lopez R, Regier J, Cole MB, Jordan MI, Yosef N (2018) Deep generative modeling for single-cell transcriptomics. Nat Methods 15(12):1053\u20131058. https:\/\/doi.org\/10.1038\/s41592-018-0229-2","journal-title":"Nat Methods"},{"key":"115_CR37","doi-asserted-by":"publisher","unstructured":"Lotfollahi M, Rybakov S, Hrovatin K, Hediyeh-zadeh S, Talavera-L\u00f3pez C, Misharin AV, Theis FJ (2023) Biologically informed deep learning to query gene programs in single-cell atlases. Nat Cell Biol. https:\/\/doi.org\/10.1038\/s41556-022-01072-x","DOI":"10.1038\/s41556-022-01072-x"},{"issue":"13","key":"115_CR38","doi-asserted-by":"publisher","first-page":"3209","DOI":"10.3390\/cancers14133209","volume":"14","author":"PC McDonald","year":"2022","unstructured":"McDonald PC, Dedhar S (2022) New perspectives on the role of integrin-linked kinase (ILK) signaling in cancer metastasis. Cancers 14(13):3209. https:\/\/doi.org\/10.3390\/cancers14133209","journal-title":"Cancers"},{"key":"115_CR39","doi-asserted-by":"publisher","unstructured":"Mitchel J, Gordon MG, Perez RK, Biederstedt E, Bueno R, Ye CJ, Kharchenko PV (2024) Coordinated, multicellular patterns of transcriptional variation that stratify patient cohorts are revealed by tensor decomposition. Nat Biotechnol. https:\/\/doi.org\/10.1038\/s41587-024-02411-z","DOI":"10.1038\/s41587-024-02411-z"},{"issue":"5","key":"115_CR40","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1096\/fba.2021-00055","volume":"4","author":"A Mohammadalipour","year":"2022","unstructured":"Mohammadalipour A, Diaz MF, Livingston M, Ewere A, Zhou A, Horton PD, Olamigoke LT et al (2022) RhoA\u2010ROCK competes with YAP to regulate amoeboid breast cancer cell migration in response to lymphatic\u2010like flow. FASEB BioAdv 4(5):342\u2013361. https:\/\/doi.org\/10.1096\/fba.2021-00055","journal-title":"FASEB BioAdv"},{"key":"115_CR41","doi-asserted-by":"publisher","unstructured":"Mooij JM, Claassen T (2020) Constraint-based causal discovery using partial ancestral graphs in the presence of cycles. PMLR. https:\/\/doi.org\/10.48550\/arXiv.2005.00610","DOI":"10.48550\/arXiv.2005.00610"},{"issue":"3","key":"115_CR42","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cell.2016.09.025","volume":"167","author":"Y N\u00e9d\u00e9lec","year":"2016","unstructured":"N\u00e9d\u00e9lec Y, Sanz J, Baharian G, Szpiech ZA, Pacis A, Dumaine A, Grenier J-C et al (2016) Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Cell 167(3):657\u2013669.e21. https:\/\/doi.org\/10.1016\/j.cell.2016.09.025","journal-title":"Cell"},{"key":"115_CR43","doi-asserted-by":"publisher","unstructured":"Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E et al (2021) Molecular subtyping of Alzheimer\u2019s disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. https:\/\/doi.org\/10.1126\/sciadv.abb5398","DOI":"10.1126\/sciadv.abb5398"},{"issue":"7","key":"115_CR44","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1038\/s41587-019-0114-2","volume":"37","author":"AM Newman","year":"2019","unstructured":"Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, Khodadoust MS et al (2019) Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol 37(7):773\u2013782. https:\/\/doi.org\/10.1038\/s41587-019-0114-2","journal-title":"Nat Biotechnol"},{"issue":"21","key":"115_CR45","doi-asserted-by":"publisher","first-page":"5222","DOI":"10.1158\/1078-0432.CCR-10-1282","volume":"16","author":"TO Nielsen","year":"2010","unstructured":"Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, Davies SR et al (2010) A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res 16(21):5222\u20135232. https:\/\/doi.org\/10.1158\/1078-0432.CCR-10-1282","journal-title":"Clin Cancer Res"},{"issue":"147","key":"115_CR46","doi-asserted-by":"publisher","first-page":"170113","DOI":"10.1183\/16000617.0113-2017","volume":"27","author":"P Paliogiannis","year":"2018","unstructured":"Paliogiannis P, Fois AG, Sotgia S, Mangoni AA, Zinellu E, Pirina P, Negri S, Carru C, Zinellu A (2018) Neutrophil to lymphocyte ratio and clinical outcomes in COPD: recent evidence and future perspectives. Eur Respir Rev 27(147):170113. https:\/\/doi.org\/10.1183\/16000617.0113-2017","journal-title":"Eur Respir Rev"},{"key":"115_CR47","unstructured":"Pan W, Doshi-Velez F (2016) A characterization of the non-uniqueness of nonnegative matrix factorizations. Preprint at. http:\/\/arxiv.org\/abs\/1604.00653"},{"key":"115_CR48","doi-asserted-by":"publisher","unstructured":"Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, He X, Perou CM (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. https:\/\/doi.org\/10.1186\/bcr2635","DOI":"10.1186\/bcr2635"},{"issue":"2","key":"115_CR49","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1007\/s41060-016-0032-z","volume":"3","author":"J Ramsey","year":"2017","unstructured":"Ramsey J, Glymour M, Sanchez-Romero R, Glymour C (2017) A million variables and more: the fast greedy equivalence search algorithm for learning high-dimensional graphical causal models, with an application to functional magnetic resonance images. Int J Data Sci Analytics 3(2):121\u2013129. https:\/\/doi.org\/10.1007\/s41060-016-0032-z","journal-title":"Int J Data Sci Analytics"},{"issue":"1","key":"115_CR50","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","volume":"160","author":"MS Rooney","year":"2015","unstructured":"Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160(1):48\u201361. https:\/\/doi.org\/10.1016\/j.cell.2014.12.033","journal-title":"Cell"},{"issue":"1","key":"115_CR51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07232-8","volume":"9","author":"SR Rosario","year":"2018","unstructured":"Rosario SR, Long MD, Affronti HC, Rowsam AM, Eng KH, Smiraglia DJ (2018) Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas. Nat Commun 9(1):5330. https:\/\/doi.org\/10.1038\/s41467-018-07232-8","journal-title":"Nat Commun"},{"issue":"7748","key":"115_CR52","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/s41586-019-1007-8","volume":"567","author":"OM Rueda","year":"2019","unstructured":"Rueda OM, Sammut S-J, Seoane JA, Chin S-F, Caswell-Jin JL, Callari M, Batra R et al (2019) Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. Nature 567(7748):399\u2013404. https:\/\/doi.org\/10.1038\/s41586-019-1007-8","journal-title":"Nature"},{"issue":"1","key":"115_CR53","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1002\/1878-0261.13047","volume":"16","author":"Rye","year":"2022","unstructured":"Rye, Hansine I, Huse K, Josefsson SE, Kildal W, Danielsen HE, Schlichting E, Garred \u00d8 et al (2022) Breast cancer metastasis: immune profiling of lymph nodes reveals exhaustion of effector T cells and immunosuppression. Mol Oncol 16(1):88\u2013103. https:\/\/doi.org\/10.1002\/1878-0261.13047","journal-title":"Mol Oncol"},{"issue":"1","key":"115_CR54","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-015-0131-9","volume":"7","author":"LH Saal","year":"2015","unstructured":"Saal LH, Vallon-Christersson J, H\u00e4kkinen J, Hegardt C, Grabau D, Winter C, Brueffer C et al (2015) The Sweden Cancerome Analysis Network-Breast (SCAN-B) initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. Genome Med 7(1):20. https:\/\/doi.org\/10.1186\/s13073-015-0131-9","journal-title":"Genome Med"},{"issue":"2","key":"115_CR55","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/ng1165","volume":"34","author":"E Segal","year":"2003","unstructured":"Segal E, Shapira M, Regev A, Pe\u2019er D, Botstein D, Koller D, Friedman N (2003) Module networks: identifying regulatory modules and their condition-specific regulators from gene expression data. Nat Genet 34(2):166\u2013176. https:\/\/doi.org\/10.1038\/ng1165","journal-title":"Nat Genet"},{"key":"115_CR56","doi-asserted-by":"publisher","unstructured":"S\u00f6derholm S, Cant\u00f9 C (2021) The WNT\/\u0392\u2010catenin dependent transcription: a tissue\u2010specific business. WIREs Mechan Dis. https:\/\/doi.org\/10.1002\/wsbm.1511","DOI":"10.1002\/wsbm.1511"},{"issue":"6473","key":"115_CR57","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1126\/science.aax6234","volume":"367","author":"SR Srivatsan","year":"2020","unstructured":"Srivatsan SR, McFaline-Figueroa JL, Ramani V, Saunders L, Cao J, Packer J, Pliner HA et al (2020) Massively multiplex chemical transcriptomics at single-cell resolution. Science 367(6473):45\u201351. https:\/\/doi.org\/10.1126\/science.aax6234","journal-title":"Science"},{"issue":"7","key":"115_CR58","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1038\/ni.2897","volume":"15","author":"FC Steinke","year":"2014","unstructured":"Steinke FC, Yu S, Zhou X, He B, Yang W, Zhou B, Kawamoto H, Zhu J, Tan K, Xue H-H (2014) TCF-1 and LEF-1 Act upstream of Th-POK to promote the CD4+ T cell fate and interact with Runx3 to silence Cd4 in CD8+ T cells. Nat Immunol 15(7):646\u2013656. https:\/\/doi.org\/10.1038\/ni.2897","journal-title":"Nat Immunol"},{"issue":"11","key":"115_CR59","doi-asserted-by":"publisher","first-page":"9747","DOI":"10.1074\/jbc.M210993200","volume":"278","author":"G Urban","year":"2003","unstructured":"Urban G, Golden T, Aragon IV, Cowsert L, Cooper SR, Dean NM, Honkanen RE (2003) Identification of a functional link for the P53 tumor suppressor protein in dexamethasone-induced growth suppression. J Biol Chem 278(11):9747\u20139753. https:\/\/doi.org\/10.1074\/jbc.M210993200","journal-title":"J Biol Chem"},{"issue":"2","key":"115_CR60","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1016\/S0092-8674(02)00709-2","volume":"109","author":"M van de Wetering","year":"2002","unstructured":"van de Wetering M, de Lau W, Clevers H (2002) WNT signaling and lymphocyte development. Cell 109(2):S13\u201319. https:\/\/doi.org\/10.1016\/S0092-8674(02)00709-2","journal-title":"Cell"},{"issue":"4","key":"115_CR61","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1183\/09031936.00111707","volume":"31","author":"J Vestbo","year":"2008","unstructured":"Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G et al (2008) Evaluation of COPD longitudinally to identify predictive surrogate end-points (ECLIPSE). Eur Respir J 31(4):869\u2013873. https:\/\/doi.org\/10.1183\/09031936.00111707","journal-title":"Eur Respir J"},{"key":"115_CR62","doi-asserted-by":"publisher","first-page":"6947","DOI":"10.2147\/CMAR.S254250","volume":"12","author":"Z Wang","year":"2020","unstructured":"Wang Z, Yu Z, Wang G-H, Zhou Y-M, Deng J-P, Feng Y, Chen J-Q, Tian L (2020) AURKB promotes the metastasis of gastric cancer, possibly by inducing EMT. Cancer Manag Res 12:6947\u20136958. https:\/\/doi.org\/10.2147\/CMAR.S254250","journal-title":"Cancer Manag Res"},{"issue":"9","key":"115_CR63","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1038\/s41588-021-00911-1","volume":"53","author":"SZ Wu","year":"2021","unstructured":"Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A, Thennavan A et al (2021) A single-cell and spatially resolved atlas of human breast cancers. Nat Genet 53(9):1334\u20131347. https:\/\/doi.org\/10.1038\/s41588-021-00911-1","journal-title":"Nat Genet"},{"key":"115_CR64","doi-asserted-by":"publisher","unstructured":"Xie Z, Bailey A, Kuleshov MV, Clarke DJB, Evangelista JE, Jenkins SL, Lachmann A et al (2021) Gene set knowledge discovery with Enrichr. Curr Protoc. https:\/\/doi.org\/10.1002\/cpz1.90","DOI":"10.1002\/cpz1.90"},{"issue":"1","key":"115_CR65","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-020-01276-5","volume":"19","author":"X Xu","year":"2020","unstructured":"Xu X, Zhang M, Xu F, Jiang S (2020) Wnt signaling in breast cancer: biological mechanisms, challenges and opportunities. Mol Cancer 19(1):165. https:\/\/doi.org\/10.1186\/s12943-020-01276-5","journal-title":"Mol Cancer"},{"issue":"1","key":"115_CR66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42748-8","volume":"14","author":"CM Young","year":"2023","unstructured":"Young CM, Beziaud L, Dessen P, Madurga Alonso A, Santamaria-Mart\u00ednez A, Huelsken J (2023) Metabolic dependencies of metastasis-initiating cells in female breast cancer. Nat Commun 14(1):7076. https:\/\/doi.org\/10.1038\/s41467-023-42748-8","journal-title":"Nat Commun"},{"issue":"7","key":"115_CR67","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giy083","volume":"7","author":"L Zappia","year":"2018","unstructured":"Zappia L, Oshlack A (2018) Clustering trees: a visualization for evaluating clusterings at multiple resolutions. GigaScience 7(7):giy083. https:\/\/doi.org\/10.1093\/gigascience\/giy083","journal-title":"GigaScience"},{"issue":"6","key":"115_CR68","doi-asserted-by":"publisher","DOI":"10.1002\/smll.202206754","volume":"19","author":"M Zhou","year":"2023","unstructured":"Zhou M, Ma Y, Chiang C-C, Rock EC, Luker KE, Luker GD, Chen Y-C (2023) High-throughput cellular heterogeneity analysis in cell migration at the single-cell level. Small 19(6):e2206754. https:\/\/doi.org\/10.1002\/smll.202206754","journal-title":"Small"}],"container-title":["Molecular Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44320-025-00115-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1038\/s44320-025-00115-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1038\/s44320-025-00115-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T23:48:58Z","timestamp":1779061738000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1038\/s44320-025-00115-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":68,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,2]]}},"alternative-id":["115"],"URL":"https:\/\/doi.org\/10.1038\/s44320-025-00115-3","relation":{},"ISSN":["1744-4292"],"issn-type":[{"value":"1744-4292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]},"assertion":[{"value":"25 September 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}