{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:53:10Z","timestamp":1782327190628,"version":"3.54.5"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":54,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170662"],"award-info":[{"award-number":["32170662"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82460142"],"award-info":[{"award-number":["82460142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Hybribio Biotech Funding","award":["H20230314"],"award-info":[{"award-number":["H20230314"]}]},{"name":"Guangdong Hybribio Biotech Funding","award":["H20230311"],"award-info":[{"award-number":["H20230311"]}]},{"name":"Guangdong Hybribio Biotech Funding","award":["H20230313"],"award-info":[{"award-number":["H20230313"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>It is important to predict cell-type-specific drug responses within the heterogeneous tumors for precision medicine. The single-cell RNA sequencing (scRNA-seq) technique together with drug responses data provides opportunities for this mission. The previous methods were mainly evaluated in datasets derived from cancer cell lines, lacking direct validations on the real tumors derived from mouse models and clinical human samples. In this work, we integrated the labeled scRNA-seq, bulk RNA, and drug response data to develop the computational tool scTumorDrug to predict cell-type-specific drug responses for heterogeneous tumors. Overall, scTumorDrug achieved accurate predictions in public datasets derived from cell lines, mouse models, and clinical human samples, and outperformed previous methods in the selected datasets. Since there is no available experimental validation on drug responses from tumor subpopulations, we established the mouse bladder tumor model to investigate the cell-type-specific drug responses for the small molecule JQ1 by performing single nucleus RNA sequencing and spatial transcriptomics. The mouse model showed that the JQ1 treatment delayed the tumor progression though it did not completely eliminate the bladder tumors. The scTumorDrug found that the Mki67+ urothelial subpopulation was sensitive to JQ1, which was cross-validated by spatial transcriptomics. This observation also provided an explanation for JQ1 efficacy. To summarize, the scTumorDrug can be used in broad application scenarios and we provided cell-type-specific drug response prediction and validation.<\/jats:p>","DOI":"10.1093\/bib\/bbag337","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:47:49Z","timestamp":1780487269000},"source":"Crossref","is-referenced-by-count":0,"title":["scTumorDrug: predicting cell-type-specific drug responses for heterogeneous tumors"],"prefix":"10.1093","volume":"27","author":[{"given":"Qiang","family":"Zhang","sequence":"first","affiliation":[{"name":"Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University , Easter Outer Ring Road, Chenggong District, Kunming 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University , Easter Outer Ring Road, Chenggong District, Kunming 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunming","family":"Guo","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University , Easter Outer Ring Road, Chenggong District, Kunming 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0448-0094","authenticated-orcid":false,"given":"Cheng","family":"Peng","sequence":"additional","affiliation":[{"name":"Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University , Easter Outer Ring Road, Chenggong District, Kunming 650500 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"2026062414281242100_ref1","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1158\/1078-0432.CCR-14-1429","article-title":"Translational implications of tumor heterogeneity","volume":"21","author":"Jamal-Hanjani","year":"2015","journal-title":"Clin Cancer Res"},{"key":"2026062414281242100_ref2","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3390\/ph9020033","article-title":"Tumor heterogeneity, single-cell sequencing, and drug resistance","volume":"9","author":"Schmidt","year":"2016","journal-title":"Pharmaceuticals"},{"key":"2026062414281242100_ref3","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.cell.2017.01.018","article-title":"Clonal heterogeneity and tumor evolution: past, present, and the future","volume":"168","author":"McGranahan","year":"2017","journal-title":"Cell"},{"key":"2026062414281242100_ref4","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1016\/j.cell.2018.06.025","article-title":"Toward minimal residual disease-directed therapy in melanoma","volume":"174","author":"Rambow","year":"2018","journal-title":"Cell"},{"key":"2026062414281242100_ref5","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"},{"key":"2026062414281242100_ref6","doi-asserted-by":"publisher","first-page":"D955","DOI":"10.1093\/nar\/gks1111","article-title":"Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells","volume":"41","author":"Yang","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2026062414281242100_ref7","doi-asserted-by":"publisher","first-page":"2993","DOI":"10.1002\/jcp.26052","article-title":"Three-dimensional cell culture models for anticancer drug screening: worth the effort?","volume":"233","author":"Verjans","year":"2018","journal-title":"J Cell Physiol"},{"key":"2026062414281242100_ref8","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.drudis.2015.08.001","article-title":"Identifying compound efficacy targets in phenotypic drug discovery","volume":"21","author":"Schirle","year":"2016","journal-title":"Drug Discov Today"},{"key":"2026062414281242100_ref9","doi-asserted-by":"publisher","first-page":"5680","DOI":"10.1038\/s41467-022-33291-z","article-title":"Gene expression based inference of cancer drug sensitivity","volume":"13","author":"Chawla","year":"2022","journal-title":"Nat Commun"},{"key":"2026062414281242100_ref10","doi-asserted-by":"publisher","first-page":"2204113","DOI":"10.1002\/advs.202204113","article-title":"Enabling single-cell drug response annotations from bulk RNA-Seq using SCAD","volume":"10","author":"Zheng","year":"2023","journal-title":"Adv Sci"},{"key":"2026062414281242100_ref11","doi-asserted-by":"publisher","first-page":"6494","DOI":"10.1038\/s41467-022-34277-7","article-title":"Deep transfer learning of cancer drug responses by integrating bulk and single-cell RNA-seq data","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"},{"key":"2026062414281242100_ref12","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s13073-021-01001-x","article-title":"Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq data","volume":"13","author":"Fustero-Torre","year":"2021","journal-title":"Genome Med"},{"key":"2026062414281242100_ref13","doi-asserted-by":"publisher","first-page":"2400991","DOI":"10.1002\/smtd.202400991","article-title":"Single cell inference of cancer drug response using pathway-based transformer network","volume":"9","author":"Yao","year":"2025","journal-title":"Small Methods"},{"key":"2026062414281242100_ref14","doi-asserted-by":"publisher","first-page":"2021","DOI":"10.1158\/0008-5472.CAN-23-3005","article-title":"Integration of pan-cancer cell line and single-cell transcriptomic profiles enables inference of therapeutic vulnerabilities in heterogeneous tumors","volume":"84","author":"Zhang","year":"2024","journal-title":"Cancer Res"},{"key":"2026062414281242100_ref15","doi-asserted-by":"publisher","first-page":"268","DOI":"10.3390\/genes14020268","article-title":"scDR: predicting drug response at single-cell resolution","volume":"14","author":"Lei","year":"2023","journal-title":"Genes"},{"key":"2026062414281242100_ref16","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1038\/nchembio.1986","article-title":"Correlating chemical sensitivity and basal gene expression reveals mechanism of action","volume":"12","author":"Rees","year":"2016","journal-title":"Nat Chem Biol"},{"key":"2026062414281242100_ref17","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1016\/j.cell.2013.08.003","article-title":"An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules","volume":"154","author":"Basu","year":"2013","journal-title":"Cell"},{"key":"2026062414281242100_ref18","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1158\/2159-8290.CD-15-0235","article-title":"Harnessing connectivity in a large-scale small-molecule sensitivity dataset","volume":"5","author":"Seashore-Ludlow","year":"2015","journal-title":"Cancer Discov"},{"key":"2026062414281242100_ref19","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1038\/s41588-020-00726-6","article-title":"Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity","volume":"52","author":"Kinker","year":"2020","journal-title":"Nat Genet"},{"key":"2026062414281242100_ref20","doi-asserted-by":"publisher","first-page":"2723","DOI":"10.1038\/s41467-019-10652-9","article-title":"Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia","volume":"10","author":"Bell","year":"2019","journal-title":"Nat Commun"},{"key":"2026062414281242100_ref21","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/s41586-018-0409-3","article-title":"Genetic and transcriptional evolution alters cancer cell line drug response","volume":"560","author":"Ben-David","year":"2018","journal-title":"Nature"},{"key":"2026062414281242100_ref22","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.ccell.2022.08.010","article-title":"Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer","volume":"40","author":"Wang","year":"2022","journal-title":"Cancer Cell"},{"key":"2026062414281242100_ref23","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1158\/1541-7786.MCR-21-0565","article-title":"Distinct transcriptional programs in ascitic and solid cancer cells induce different responses to chemotherapy in high-grade serous ovarian cancer","volume":"20","author":"Loret","year":"2022","journal-title":"Mol Cancer Res"},{"key":"2026062414281242100_ref24","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.pharmthera.2018.06.014","article-title":"More than fishing for a cure: the promises and pitfalls of high throughput cancer cell line screens","volume":"191","author":"Ling","year":"2018","journal-title":"Pharmacol Ther"},{"key":"2026062414281242100_ref25","doi-asserted-by":"publisher","first-page":"25","DOI":"10.7171\/jbt.18-2902-002","article-title":"The cellosaurus, a cell-line knowledge resource","volume":"29","author":"Bairoch","year":"2018","journal-title":"J Biomol Tech"},{"key":"2026062414281242100_ref26","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1038\/s41467-018-07931-2","article-title":"Single-cell RNA-seq denoising using a deep count autoencoder","volume":"10","author":"Eraslan","year":"2019","journal-title":"Nat Commun"},{"key":"2026062414281242100_ref27","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"2026062414281242100_ref28","doi-asserted-by":"publisher","first-page":"1396","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":"2026062414281242100_ref29","doi-asserted-by":"publisher","first-page":"100141","DOI":"10.1016\/j.xinn.2021.100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation (Camb)"},{"key":"2026062414281242100_ref30","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1038\/ncb2956","article-title":"Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma","volume":"16","author":"Shin","year":"2014","journal-title":"Nat Cell Biol"},{"key":"2026062414281242100_ref31","doi-asserted-by":"publisher","first-page":"2734","DOI":"10.1038\/s41467-023-38409-5","article-title":"High-throughput single nucleus total RNA sequencing of formalin-fixed paraffin-embedded tissues by snRandom-seq","volume":"14","author":"Xu","year":"2023","journal-title":"Nat Commun"},{"key":"2026062414281242100_ref32","doi-asserted-by":"publisher","article-title":"Spatial total RNA sequencing of formalin-fixed paraffin embedded tissues by spRandom-seq","author":"Liao","DOI":"10.1101\/2025.02.19.638981"},{"key":"2026062414281242100_ref33","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade","volume":"357","author":"Le","year":"2017","journal-title":"Science"},{"key":"2026062414281242100_ref34","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/nature10509","article-title":"Chung C-w, Hopf C, Savitski MM: inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia","volume":"478","author":"Dawson","year":"2011","journal-title":"Nature"},{"key":"2026062414281242100_ref35","doi-asserted-by":"publisher","first-page":"7501","DOI":"10.1021\/jm401088k","article-title":"Discovery of epigenetic regulator I-BET762: lead optimization to afford a clinical candidate inhibitor of the BET bromodomains","volume":"56","author":"Mirguet","year":"2013","journal-title":"J Med Chem"},{"key":"2026062414281242100_ref36","doi-asserted-by":"publisher","first-page":"e503","DOI":"10.1038\/bcj.2016.112","article-title":"The role of the proteasome in AML","volume":"6","author":"Csizmar","year":"2016","journal-title":"Blood Cancer J"},{"key":"2026062414281242100_ref37","doi-asserted-by":"publisher","first-page":"8955","DOI":"10.3390\/ijms22168955","article-title":"The proteasome inhibitor bortezomib induces apoptosis and activation in gel-filtered human platelets","volume":"22","author":"Ghansah","year":"2021","journal-title":"Int J Mol Sci"},{"key":"2026062414281242100_ref38","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1016\/j.chembiol.2009.11.015","article-title":"Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites","volume":"16","author":"Britton","year":"2009","journal-title":"Chem Biol"},{"key":"2026062414281242100_ref39","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1038\/sj.cdd.4402297","article-title":"Proteasome inhibition drastically but reversibly impairs murine lymphocyte development","volume":"15","author":"Maseda","year":"2008","journal-title":"Cell Death Differ"},{"key":"2026062414281242100_ref40","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1016\/j.molcel.2014.05.016","article-title":"The mechanisms behind the therapeutic activity of BET bromodomain inhibition","volume":"54","author":"Shi","year":"2014","journal-title":"Mol Cell"},{"key":"2026062414281242100_ref41","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/20974","article-title":"Structure and ligand of a histone acetyltransferase bromodomain","volume":"399","author":"Dhalluin","year":"1999","journal-title":"Nature"},{"key":"2026062414281242100_ref42","doi-asserted-by":"publisher","first-page":"8538","DOI":"10.1073\/pnas.95.15.8538","article-title":"Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways","volume":"95","author":"Jiang","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026062414281242100_ref43","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.molcel.2005.06.029","article-title":"Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4","volume":"19","author":"Yang","year":"2005","journal-title":"Mol Cell"},{"key":"2026062414281242100_ref44","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1038\/nature09504","article-title":"Selective inhibition of BET bromodomains","volume":"468","author":"Filippakopoulos","year":"2010","journal-title":"Nature"},{"key":"2026062414281242100_ref45","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1038\/sj.onc.1210852","article-title":"BRD\u2013NUT oncoproteins: a family of closely related nuclear proteins that block epithelial differentiation and maintain the growth of carcinoma cells","volume":"27","author":"French","year":"2008","journal-title":"Oncogene"},{"key":"2026062414281242100_ref46","doi-asserted-by":"publisher","first-page":"16669","DOI":"10.1073\/pnas.1108190108","article-title":"Targeting MYC dependence in cancer by inhibiting BET bromodomains","volume":"108","author":"Mertz","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026062414281242100_ref47","doi-asserted-by":"publisher","first-page":"9442","DOI":"10.18632\/oncotarget.24253","article-title":"PTPRG and PTPRC modulate nilotinib response in chronic myeloid leukemia cells","volume":"9","author":"Drube","year":"2018","journal-title":"Oncotarget"},{"key":"2026062414281242100_ref48","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1146\/annurev-immunol-110519-071134","article-title":"Insights gained from single-cell analysis of immune cells in the tumor microenvironment","volume":"39","author":"Ren","year":"2021","journal-title":"Annu Rev Immunol"},{"key":"2026062414281242100_ref49","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1042\/BST20231427","article-title":"Mechanoimmunology in the solid tumor microenvironment","volume":"52","author":"Golo","year":"2024","journal-title":"Biochem Soc Trans"},{"key":"2026062414281242100_ref50","doi-asserted-by":"publisher","first-page":"215888","DOI":"10.1016\/j.canlet.2022.215888","article-title":"The tumor microenvironment's role in malignant progression and treatment response","volume":"548","author":"Frankiw","year":"2022","journal-title":"Cancer Lett"}],"container-title":["Briefings in Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/27\/3\/bbag337\/68607353\/bbag337.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bib\/article-pdf\/27\/3\/bbag337\/68607353\/bbag337.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:28:18Z","timestamp":1782325698000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bib\/article\/doi\/10.1093\/bib\/bbag337\/8715717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5]]},"references-count":50,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,5,4]]}},"URL":"https:\/\/doi.org\/10.1093\/bib\/bbag337","relation":{},"ISSN":["1467-5463","1477-4054"],"issn-type":[{"value":"1467-5463","type":"print"},{"value":"1477-4054","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,5]]},"article-number":"bbag337"}}