{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:12:42Z","timestamp":1788423162092,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Colorectal cancer (CRC) comprises heterogeneous malignant epithelial states, but it remains unclear which transcriptional programs recur across patients and how these programs relate to the immune context.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated five public single-cell RNA-sequencing datasets comprising 425,402 cells from 119 patients using scVI, defined malignant epithelial cells with inferCNV, and characterized their states and transcriptional programs using cNMF, pySCENIC, and CytoTRACE2. Program recurrence was assessed by rerunning cNMF separately for individual patients. Metaprogram associations were subsequently evaluated in bulk cohorts, CRC cell lines, spatial transcriptomic datasets, and an immune-checkpoint inhibitor (ICI) cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified five malignant epithelial states and eight metaprograms. MP7, a secretory\/goblet-lineage program, was independently recovered in 9 of 26 evaluable patients across three datasets, with reciprocal-best matches in five. Although its top-100 gene profile closely resembled that of normal goblet cells (Spearman r = 0.834), 92.2\u201394.2% of MP7-dominant cells were retained as malignant under stricter classification criteria. Bulk MP7 scores were sensitive to epithelial composition, and an exploratory 17-gene survival score derived from MP7 showed limited discrimination in nested cross-validation and external cohorts. SERINC2 was prioritized from this gene set for functional testing. SERINC2-targeting shRNAs increased wound closure and Transwell invasion in SW480 and RKO cells, with RNA-level knockdown confirmed in SW480 cells. MP7 and SERINC2 showed context-dependent associations with immune features at the patient and spatial levels, but neither distinguished response in the examined ICI cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>MP7 represents a secretory\/goblet-lineage program that recurs in a subset of CRC tumors rather than a broadly shared malignant state. The findings also identify SERINC2 as a candidate regulator of CRC cell motility and invasion, although its mechanism and clinical relevance require further validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1918381","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:19:11Z","timestamp":1788419951000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated single-cell analysis characterizes malignant epithelial programs and context-dependent immune associations of MP7\/SERINC2 in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Wei","family":"Ying","sequence":"first","affiliation":[{"name":"Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastric Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Radiotherapy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","year":"2012","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30789-X","article-title":"International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study","volume":"391","author":"Pag\u00e8s","year":"2018","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andr\u00e9","year":"2020","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3967","article-title":"The consensus molecular subtypes of colorectal cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01100-4","article-title":"Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer","volume":"54","author":"Joanito","year":"2022","journal-title":"Nat Genet"},{"key":"B7","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/s41588-020-0636-z","article-title":"Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer","volume":"52","author":"Lee","year":"2020","journal-title":"Nat Genet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114123","article-title":"Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer","volume":"13","author":"Uhlitz","year":"2021","journal-title":"EMBO Mol Med"},{"key":"B9","doi-asserted-by":"publisher","first-page":"4734","DOI":"10.1016\/j.cell.2021.08.003","article-title":"Spatially organized multicellular immune hubs in human colorectal cancer","volume":"184","author":"Pelka","year":"2021","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s13059-022-02677-z","article-title":"Refining colorectal cancer classification and clinical stratification through a single-cell atlas","volume":"23","author":"Khaliq","year":"2022","journal-title":"Genome Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-1445","article-title":"Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers","volume":"14","author":"Liu","year":"2024","journal-title":"Cancer Discov"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.43803","article-title":"Identifying gene expression programs of cell-type identity and cellular activity with single-cell RNA-seq","volume":"8","author":"Kotliar","year":"2019","journal-title":"Elife"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat Methods"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-020-0336-2","article-title":"A scalable SCENIC workflow for single-cell gene regulatory network analysis","volume":"15","author":"Van de Sande","year":"2020","journal-title":"Nat Protoc"},{"key":"B15","doi-asserted-by":"publisher","first-page":"4159","DOI":"10.1016\/j.cell.2026.04.028","article-title":"D-SPIN constructs regulatory network models from scRNA-seq that reveal organizing principles of perturbation response","volume":"189","author":"Jiang","year":"2026","journal-title":"Cell"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-009-0467-y","article-title":"An expression module of WIPF1-coexpressed genes identifies patients with favorable prognosis in three tumor types","volume":"87","author":"Staub","year":"2009","journal-title":"J Mol Med (Berl)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0103159","article-title":"Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study","volume":"9","author":"Kirzin","year":"2014","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001453","article-title":"Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value","volume":"10","author":"Marisa","year":"2013","journal-title":"PLoS Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.11.005","article-title":"Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer","volume":"138","author":"Smith","year":"2010","journal-title":"Gastroenterology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.cels.2018.11.005","article-title":"Scrublet: computational identification of cell doublets in single-cell transcriptomic data","volume":"8","author":"Wolock","year":"2019","journal-title":"Cell Syst"},{"key":"B21","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.cels.2020.05.010","article-title":"Solo: doublet identification in single-cell RNA-seq via semi-supervised deep learning","volume":"11","author":"Bernstein","year":"2020","journal-title":"Cell Syst"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0229-2","article-title":"Deep generative modeling for single-cell transcriptomics","volume":"15","author":"Lopez","year":"2018","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254257","article-title":"Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"Patel","year":"2014","journal-title":"Science"},{"key":"B24","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/s42003-025-07942-y","article-title":"scMalignantFinder distinguishes Malignant cells in single-cell and spatial transcriptomics by leveraging cancer signatures","volume":"8","author":"Yu","year":"2025","journal-title":"Commun Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-025-02857-2","article-title":"Improved reconstruction of single-cell developmental potential with CytoTRACE 2","volume":"22","author":"Kang","year":"2025","journal-title":"Nat Methods"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","article-title":"GSVA: gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"H\u00e4nzelmann","year":"2013","journal-title":"BMC Bioinf"},{"key":"B29","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1186\/s13059-016-1070-5","article-title":"Estimating the population abundance of tissue-infiltrating immune and stromal cell populations using gene expression","volume":"17","author":"Becht","year":"2016","journal-title":"Genome Biol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"16618","DOI":"10.1038\/s41598-017-16747-x","article-title":"CMScaller: an R package for consensus molecular subtyping of colorectal cancer pre-clinical models","volume":"7","author":"Eide","year":"2017","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization paths for generalized linear models via coordinate descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J Stat Softw"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1214\/08-AOAS169","article-title":"Random survival forests","volume":"2","author":"Ishwaran","year":"2008","journal-title":"Ann Appl Stat"},{"key":"B33","doi-asserted-by":"crossref","DOI":"10.1145\/2939672.2939785","article-title":"XGBoost: a scalable tree boosting system","author":"Chen","year":"2016"},{"key":"B34","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s42256-019-0138-9","article-title":"From local explanations to global understanding with explainable AI for trees","volume":"2","author":"Lundberg","year":"2020","journal-title":"Nat Mach Intell"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-14","article-title":"Allowing for mandatory covariates in boosting estimation of sparse high-dimensional survival models","volume":"9","author":"Binder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B36","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale single-cell gene expression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome Biol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-024-01515-9","article-title":"Tumor-immune hybrid cells evade the immune response and potentiate colorectal cancer metastasis through CTLA4","volume":"25","author":"Tanjak","year":"2025","journal-title":"Clin Exp Med"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.ccell.2024.06.009","article-title":"Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer","volume":"42","author":"Chen","year":"2024","journal-title":"Cancer Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1193665","article-title":"Non-coding RNAs and gastrointestinal cancers prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies","volume":"13","author":"Zha","year":"2023","journal-title":"Front Oncol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S157493","article-title":"Prognostic value of microRNAs in colorectal cancer: a meta-analysis","volume":"10","author":"Gao","year":"2018","journal-title":"Cancer Manag Res"},{"key":"B41","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1186\/s12885-019-6136-9","article-title":"A pair-wise meta-analysis highlights circular RNAs as potential biomarkers for colorectal cancer","volume":"19","author":"Li","year":"2019","journal-title":"BMC Cancer"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M505712200","article-title":"Serinc, an activity-regulated protein family, incorporates serine into membrane lipid synthesis","volume":"280","author":"Inuzuka","year":"2005","journal-title":"J Biol Chem"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2018.9403","article-title":"SERINC2-knockdown inhibits proliferation, migration and invasion in lung adenocarcinoma","volume":"16","author":"Zeng","year":"2018","journal-title":"Oncol Lett"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.70296","article-title":"Serinc2 drives the progression of cervical cancer through regulating Myc pathway","volume":"13","author":"Wang","year":"2024","journal-title":"Cancer Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.105572","article-title":"SERINC2-mediated serine metabolism promotes cervical cancer progression and drives T cell exhaustion","volume":"21","author":"Sun","year":"2025","journal-title":"Int J Biol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1918381\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:19:12Z","timestamp":1788419952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1918381\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1918381"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1918381","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"article-number":"1918381"}}