{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:08:49Z","timestamp":1785431329867,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011787","name":"Heilongjiang Provincial Science and Technology Department","doi-asserted-by":"publisher","award":["LH2021F043"],"award-info":[{"award-number":["LH2021F043"]}],"id":[{"id":"10.13039\/501100011787","id-type":"DOI","asserted-by":"publisher"}]},{"award":["LH2021F043"],"award-info":[{"award-number":["LH2021F043"]}],"id":[{"id":"https:\/\/ror.org\/031tatj48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dormancy is an important factor influencing colorectal cancer (CRC) metastasis through diverse metabolic pathways and cell types. To elucidate its molecular mechanisms, bulk transcriptomic pathway scoring was integrated with single-cell RNA sequencing of epithelial, cancer stem, and immune cells to identify CRC dormancy-associated genes (CDAGs). Twenty-three CDAGs were identified. These genes were found to play a regulatory role in dormancy by participating in metabolic processes affecting energy supply or substance synthesis. In two independent CRC cohorts (GSE41258, GSE41568), machine learning models using these genes distinguished metastatic samples with area under the curve (AUC) of 0.79\u20130.87. High CDAG expression was associated with better recurrence-free survival in GSE41258 (p = 0.005), which remained significant after adjusting for age, sex, and adjuvant chemotherapy (p = 0.037). The prognostic value was validated in The Cancer Genome Atlas (TCGA) Colon and Rectal Cancer for progression-free survival (p = 0.004). Moreover, 20 CRC dormancy-associated drugs were identified, 12 of which were reported to be associated with CRC, two with experimental evidence of inhibiting CRC metastasis or recurrence. This study provided metabolic-oriented genes for characterizing CRC dormancy, which could distinguish metastatic samples and had independent prognostic value, and offered a foundation for further development of targeted therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27125191","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:43:54Z","timestamp":1780965834000},"page":"5191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined Analysis of Bulk and Single-Cell Transcriptomic Data Reveals Dormancy-Associated Genes in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Xiaoxi","family":"Wang","sequence":"first","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6704-7168","authenticated-orcid":false,"given":"Shiyi","family":"Fang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubo","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlong","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Lv","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9797-0315","authenticated-orcid":false,"given":"Wan","family":"Li","sequence":"additional","affiliation":[{"name":"College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104822","DOI":"10.1016\/j.critrevonc.2025.104822","article-title":"Regulatory mechanisms and therapeutic targeting of metastatic tumor dormancy in colorectal cancer: A comprehensive review","volume":"213","author":"Chen","year":"2025","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Qin, Y., Zhang, J., Xiao, Y., Zhang, Y., Liu, W., and Luo, X. (2026). Decoding the metabolic cipher of dormant cancer cells: Molecular mechanisms and therapeutic potentials. Cell Commun. Signal.","DOI":"10.1186\/s12964-026-02933-w"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.trecan.2024.10.005","article-title":"Metabolic landscape of disseminated cancer dormancy","volume":"11","author":"Drapela","year":"2025","journal-title":"Trends Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lewis, D.A., and Ly, T. (2021). Cell Cycle Entry Control in Na\u00efve and Memory CD8+ T Cells. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.727441"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"167312","DOI":"10.1016\/j.bbadis.2024.167312","article-title":"Metabolic adaptation in epithelial ovarian cancer metastasis","volume":"1870","author":"Frederick","year":"2024","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_6","first-page":"279","article-title":"Cell morphology in the dormancy and proliferation stage of colorectal cancer stem cells","volume":"17","author":"Liu","year":"2014","journal-title":"Zhonghua Wei Chang Wai Ke Za Zhi"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1760","DOI":"10.1182\/bloodadvances.2017004960","article-title":"Bone marrow sites differently imprint dormancy and chemoresistance to T-cell acute lymphoblastic leukemia","volume":"1","author":"Cahu","year":"2017","journal-title":"Blood Adv."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Huang, C.Y., Huang, C.Y., Pai, Y.C., Lin, B.R., Lee, T.C., Liang, P.H., and Yu, L.C. (2019). Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.01282"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5079","DOI":"10.1007\/s00216-019-01872-5","article-title":"LC-MS-based lipid profile in colorectal cancer patients: TAGs are the main disturbed lipid markers of colorectal cancer progression","volume":"411","author":"Liu","year":"2019","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s12967-024-04934-0","article-title":"Wnt\/beta-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer","volume":"22","author":"Huang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1111\/cas.16117","article-title":"Cell cycle heterogeneity and plasticity of colorectal cancer stem cells","volume":"115","author":"Higa","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1038\/s41586-022-05043-y","article-title":"Cell-matrix interface regulates dormancy in human colon cancer stem cells","volume":"608","author":"Ohta","year":"2022","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"104594","DOI":"10.1016\/j.cellimm.2022.104594","article-title":"Regulatory network of BLIMP1, IRF4, and XBP1 triad in plasmacytic differentiation and multiple myeloma pathogenesis","volume":"380","author":"Tang","year":"2022","journal-title":"Cell. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.3892\/ol.2023.14187","article-title":"Role of interleukin-32 in cancer progression (Review)","volume":"27","author":"Meng","year":"2024","journal-title":"Oncol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Singh, S., Arcaroli, J., Chen, Y., Thompson, D.C., Messersmith, W., Jimeno, A., and Vasiliou, V. (2015). ALDH1B1 Is Crucial for Colon Tumorigenesis by Modulating Wnt\/beta-Catenin, Notch and PI3K\/Akt Signaling Pathways. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121648"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12943-024-01939-7","article-title":"LINC01852 inhibits the tumorigenesis and chemoresistance in colorectal cancer by suppressing SRSF5-mediated alternative splicing of PKM","volume":"23","author":"Bian","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2616","DOI":"10.1159\/000495934","article-title":"Expression of PRDX6 Correlates with Migration and Invasiveness of Colorectal Cancer Cells","volume":"51","author":"Huang","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kudryavtseva, A.V., Fedorova, M.S., Zhavoronkov, A., Moskalev, A.A., Zasedatelev, A.S., Dmitriev, A.A., Sadritdinova, A.F., Karpova, I.Y., Nyushko, K.M., and Kalinin, D.V. (2016). Effect of lentivirus-mediated shRNA inactivation of HK1, HK2, and HK3 genes in colorectal cancer and melanoma cells. BMC Genet., 17.","DOI":"10.1186\/s12863-016-0459-1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s10238-024-01479-w","article-title":"Identification of PFKFB3 as a key factor in the development of colorectal cancer and immunotherapy resistance","volume":"24","author":"Lu","year":"2024","journal-title":"Clin. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s00232-005-0777-0","article-title":"N-methyl-D-aspartate receptor in human prostate cancer","volume":"205","author":"Abdul","year":"2005","journal-title":"J. Membr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12935-025-03712-2","article-title":"Repurposing pitavastatin and atorvastatin to overcome chemoresistance of metastatic colorectal cancer under high glucose conditions","volume":"25","author":"Cheng","year":"2025","journal-title":"Cancer Cell Int."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Anwer, S.T., Mobashir, M., Fantoukh, O.I., Khan, B., Imtiyaz, K., Naqvi, I.H., and Rizvi, M.M.A. (2022). Synthesis of Silver Nano Particles Using Myricetin and the In-Vitro Assessment of Anti-Colorectal Cancer Activity: In-Silico Integration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911024"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/mco2.83","article-title":"Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K\/Akt\/mTOR signaling pathway","volume":"2","author":"Tan","year":"2021","journal-title":"MedComm"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fuentes-Baile, M., Ventero, M.P., Encinar, J.A., Garcia-Morales, P., Poveda-Deltell, M., Perez-Valenciano, E., Barbera, V.M., Gallego-Plazas, J., Rodriguez-Lescure, A., and Martin-Nieto, J. (2020). Differential Effects of IGF-1R Small Molecule Tyrosine Kinase Inhibitors BMS-754807 and OSI-906 on Human Cancer Cell Lines. Cancers, 12.","DOI":"10.3390\/cancers12123717"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nrc3793","article-title":"Mechanisms of disseminated cancer cell dormancy: An awakening field","volume":"14","author":"Sosa","year":"2014","journal-title":"Nat. Rev. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1423-0127-20-23","article-title":"Remodeling of calcium signaling in tumor progression","volume":"20","author":"Chen","year":"2013","journal-title":"J. Biomed. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/2162-3619-2-29","article-title":"Tumor dormancy: Potential therapeutic target in tumor recurrence and metastasis prevention","volume":"2","author":"Wang","year":"2013","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1038\/s41416-023-02401-z","article-title":"A cell cycle centric view of tumour dormancy","volume":"129","author":"Weston","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.4161\/cc.5.16.3109","article-title":"Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy","volume":"5","author":"Ranganathan","year":"2006","journal-title":"Cell Cycle"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nrc2256","article-title":"Models, mechanisms and clinical evidence for cancer dormancy","volume":"7","year":"2007","journal-title":"Nat. Rev. Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41419-022-04606-1","article-title":"Nanog mediated by FAO\/ACLY signaling induces cellular dormancy in colorectal cancer cells","volume":"13","author":"Zhang","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1186\/s13046-024-03095-8","article-title":"A novel lncRNA LOC101928222 promotes colorectal cancer angiogenesis by stabilizing HMGCS2 mRNA and increasing cholesterol synthesis","volume":"43","author":"Chang","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1152\/physiolgenomics.00068.2020","article-title":"Cell dormancy plasticity: Quiescence deepens into senescence through a dimmer switch","volume":"52","author":"Fujimaki","year":"2020","journal-title":"Physiol. Genom."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s11033-025-10510-6","article-title":"Ribonucleotide-diphosphate reductase subunit M2 (RRM2) expression and colorectal cancer invasiveness: A potential prognostic biomarker","volume":"52","author":"Yazdanian","year":"2025","journal-title":"Mol. Biol. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115116","DOI":"10.1016\/j.celrep.2024.115116","article-title":"IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth","volume":"44","author":"Zhou","year":"2025","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1038\/ncb3255","article-title":"6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling","volume":"17","author":"Lin","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1038\/s41416-022-01835-1","article-title":"TXN inhibitor impedes radioresistance of colorectal cancer cells with decreased ALDH1L2 expression via TXN\/NF-kappaB signaling pathway","volume":"127","author":"Yu","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/1878-0261.12408","article-title":"SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer","volume":"13","author":"Shi","year":"2019","journal-title":"Mol. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e1352","DOI":"10.1002\/ctm2.1352","article-title":"AF9 sustains glycolysis in colorectal cancer via H3K9ac-mediated PCK2 and FBP1 transcription","volume":"13","author":"He","year":"2023","journal-title":"Clin. Transl. Med."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Klepinin, A., Zhang, S., Klepinina, L., Rebane-Klemm, E., Terzic, A., Kaambre, T., and Dzeja, P. (2020). Adenylate Kinase and Metabolic Signaling in Cancer Cells. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.00660"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1007\/s10555-023-10118-x","article-title":"Mechanisms of action of NME metastasis suppressors\u2014A family affair","volume":"42","author":"Prunier","year":"2023","journal-title":"Cancer Metastasis Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/978-1-4939-3578-9_5","article-title":"The Gene Expression Omnibus Database","volume":"1418","author":"Clough","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1084\/jem.20171385","article-title":"Itraconazole targets cell cycle heterogeneity in colorectal cancer","volume":"215","author":"Buczacki","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e169576","DOI":"10.1172\/JCI169576","article-title":"Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer","volume":"134","author":"Berlin","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.1158\/0008-5472.CAN-21-0933","article-title":"Liver Colonization by Colorectal Cancer Metastases Requires YAP-Controlled Plasticity at the Micrometastatic Stage","volume":"82","author":"Heinz","year":"2022","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.cellsig.2017.09.018","article-title":"Logarithmic expansion of LGR5(+) cells in human colorectal cancer","volume":"42","author":"Martin","year":"2018","journal-title":"Cell Signal."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Lu, M., Zessin, A.S., Glover, W., and Hsu, D.S. (2017). Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169439"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2018.03.022","article-title":"Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer","volume":"173","author":"Hoadley","year":"2018","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"D583","DOI":"10.1093\/nar\/gkac831","article-title":"GotEnzymes: An extensive database of enzyme parameter predictions","volume":"51","author":"Li","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"157\u2013172; discussion 207\u2013212","DOI":"10.1002\/sim.2929","article-title":"Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond","volume":"27","author":"Pencina","year":"2008","journal-title":"Stat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5191\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T04:29:09Z","timestamp":1781324949000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/12\/5191"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["ijms27125191"],"URL":"https:\/\/doi.org\/10.3390\/ijms27125191","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]}}}