Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas
Abstract
Single-cell RNA sequencing (scRNA-seq) enables the systematic identification of cell populations in a tissue, but characterizing their spatial organization remains challenging. We combine a microarray-based spatial transcriptomics method that reveals spatial patterns of gene expression using an array of spots, each capturing the transcriptomes of multiple adjacent cells, with scRNA-Seq generated from the same sample. To annotate the precise cellular composition of distinct tissue regions, we introduce a method for multimodal intersection analysis. Applying multimodal intersection analysis to primary pancreatic tumors, we find that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types. Furthermore, we identify colocalization of inflammatory fibroblasts and cancer cells expressing a stress-response gene module. Our approach for mapping the architecture of scRNA-seq-defined subpopulations can be applied to reveal the interactions inherent to complex tissues.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A similar function has been employed in SpatialDE.
“A similar function has been employed in SpatialDE 13 .”
From SpaGCN: Integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network (2021) · cites this paper as [13]
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709 · see citing works
Spatial reconstruction of single-cell gene expression data
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F., & Regev, A. (2015) · Nature Biotechnology · doi:10.1038/nbt.3192 · Cited by 7,055 · see citing works
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma
Patel, A. P., Tirosh, I., Trombetta, J. J., Shalek, A. K., Gillespie, S. M., Wakimoto, H., Cahill, D. P., Nahed, B. V., Curry, W. T., Martuza, R. L., et al. (2014) · Science · doi:10.1126/science.1254257 · Cited by 5,063 · see citing works
Visualization and analysis of gene expression in tissue sections by spatial transcriptomics
Ståhl, P. L., Salmén, F., Vickovic, S., Lundmark, A., Navarro, J. F., Magnusson, J., Giacomello, S., Asp, M., Westholm, J. O., Huss, M., et al. (2016) · Science · doi:10.1126/science.aaf2403 · Cited by 3,834 · see citing works
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590 · see citing works
Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms
Rőszer, T. (2015) · Mediators of Inflammation · doi:10.1155/2015/816460 · Cited by 1,762 · see citing works
Comparative Analysis of Single-Cell RNA Sequencing Methods
Ziegenhain, C., Vieth, B., Parekh, S., Reinius, B., Guillaumet-Adkins, A., Smets, M., Leonhardt, H., Heyn, H., Hellmann, I., & Enard, W. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.023 · Cited by 1,494 · see citing works
Single-cell RNA-seq enables comprehensive tumour and immune cell profiling in primary breast cancer
Chung, W., Eum, H. H., Lee, H.-O., Lee, K.-M., Lee, H.-B., Kim, K.-T., Ryu, H. S., Kim, S., Lee, J. E., Park, Y. H., et al. (2017) · Nature Communications · doi:10.1038/ncomms15081 · Cited by 992 · see citing works
Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis
Maniatis, S., Äijö, T., Vickovic, S., Braine, C., Kang, K., Mollbrink, A., Fagegaltier, D., Andrusivová, Ž., Saarenpää, S., Saiz-Castro, G., et al. (2019) · Science · doi:10.1126/science.aav9776 · Cited by 429 · see citing works
May, D., Itin, A., Gal, O., Kalinski, H., Feinstein, E., & Keshet, E. (2005) · Oncogene · doi:10.1038/sj.onc.1208325 · Cited by 167 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Exploring tissue architecture using spatial transcriptomics
Rao, A., Barkley, D., França, G. S., & Yanai, I. (2021) · Nature · doi:10.1038/s41586-021-03634-9 · Cited by 1,700 · see citing works
Self-citationRobust decomposition of cell type mixtures in spatial transcriptomics
Cable, D. M., Murray, E., Zou, L. S., Goeva, A., Macosko, E. Z., Chen, F., & Irizarry, R. A. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-00830-w · Cited by 1,487 · see citing works
Cell2location maps fine-grained cell types in spatial transcriptomics
Kleshchevnikov, V., Shmatko, A., Dann, E., Aivazidis, A., King, H. W., Li, T., Elmentaite, R., Lomakin, A., Kedlian, V., Gayoso, A., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-01139-4 · Cited by 1,279 · see citing works
Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex
Maynard, K. R., Collado-Torres, L., Weber, L. M., Uytingco, C., Barry, B. K., Williams, S. R., Catallini, J. L., Tran, M. N., Besich, Z., Tippani, M., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-020-00787-0 · Cited by 1,222 · see citing works
Deciphering cell–cell interactions and communication from gene expression
Armingol, E., Officer, A., Harismendy, O., & Lewis, N. E. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-020-00292-x · Cited by 1,267 · see citing works
Hu, J., Li, X., Coleman, K., Schroeder, A., Ma, N., Irwin, D. J., Lee, E. B., Shinohara, R. T., & Li, M. (2021) · Nature Methods · doi:10.1038/s41592-021-01255-8 · Cited by 1,113 · see citing works
Integrating single-cell and spatial transcriptomics to elucidate intercellular tissue dynamics
Longo, S. K., Guo, M. G., Ji, A. L., & Khavari, P. A. (2021) · Nature Reviews Genetics · doi:10.1038/s41576-021-00370-8 · Cited by 1,059 · see citing works
Elosua-Bayes, M., Nieto, P., Mereu, E., Gut, I., & Heyn, H. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkab043 · Cited by 732 · see citing works
Spatially resolved transcriptomes—next generation tools for tissue exploration
Asp, M., Bergenstråhle, J., & Lundeberg, J. (2020) · BioEssays · doi:10.1002/bies.201900221 · Cited by 666 · see citing works
From bulk, single-cell to spatial RNA sequencing
Li, X., & Wang, C.-Y. (2021) · International Journal of Oral Science · doi:10.1038/s41368-021-00146-0 · Cited by 605 · see citing works
Deep Visual Proteomics defines single-cell identity and heterogeneity
Mund, A., Coscia, F., Kriston, A., Hollandi, R., Kovács, F., Brunner, A.-D., Migh, E., Schweizer, L., Santos, A., Bzorek, M., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-022-01302-5 · Cited by 562 · see citing works
Barkley, D., Moncada, R., Pour, M., Liberman, D. A., Dryg, I., Werba, G., Wang, W., Baron, M., Rao, A., Xia, B., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01141-9 · Cited by 532 · see citing works
Self-citationFu, T., Dai, L.-J., Wu, S.-Y., Xiao, Y., Ma, D., Jiang, Y.-Z., & Shao, Z.-M. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01103-4 · Cited by 480 · see citing works
Li, B., Zhang, W., Guo, C., Xu, H., Li, L., Fang, M., Hu, Y., Zhang, X., Yao, X., Tang, M., et al. (2022) · Nature Methods · doi:10.1038/s41592-022-01480-9 · Cited by 459 · see citing works
Andersson, A., Larsson, L., Stenbeck, L., Salmén, F., Ehinger, A., Wu, S. Z., Al-Eryani, G., Roden, D., Swarbrick, A., Borg, Å., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26271-2 · Cited by 404 · see citing works
Hwang, W. L., Jagadeesh, K. A., Guo, J. A., Hoffman, H. I., Yadollahpour, P., Reeves, J. W., Mohan, R., Drokhlyansky, E., Van Wittenberghe, N., Ashenberg, O., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01134-8 · Cited by 426 · see citing works
Alignment and integration of spatial transcriptomics data
Zeira, R., Land, M., Strzalkowski, A., & Raphael, B. J. (2022) · Nature Methods · doi:10.1038/s41592-022-01459-6 · Cited by 298 · see citing works
Impact of the Human Cell Atlas on medicine
Rood, J. E., Maartens, A., Hupalowska, A., Teichmann, S. A., & Regev, A. (2022) · Nature Medicine · doi:10.1038/s41591-022-02104-7 · Cited by 222 · see citing works
Super-resolved spatial transcriptomics by deep data fusion
Bergenstråhle, L., He, B., Bergenstråhle, J., Abalo, X., Mirzazadeh, R., Thrane, K., Ji, A. L., Andersson, A., Larsson, L., Stakenborg, N., et al. (2022) · Nature Biotechnology · doi:10.1038/s41587-021-01075-3 · Cited by 188 · see citing works
Statistical and machine learning methods for spatially resolved transcriptomics data analysis
Zeng, Z., Li, Y., Li, Y., & Luo, Y. (2022) · Genome Biology · doi:10.1186/s13059-022-02653-7 · Cited by 186 · see citing works
Levy-Jurgenson, A., Tekpli, X., Kristensen, V. N., & Yakhini, Z. (2020) · Scientific Reports · doi:10.1038/s41598-020-75708-z · Cited by 155 · see citing works
Han, B., Zhou, S., Zhang, Y., Chen, S., Xi, W., Liu, C., Zhou, X., Yuan, M., Yu, X., Li, L., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg1323 · Cited by 143 · see citing works
TREM2 macrophages induced by human lipids drive inflammation in acne lesions
Do, T. H., Ma, F., Andrade, P. R., Teles, R., de Andrade Silva, B. J., Hu, C., Espinoza, A., Hsu, J.-E., Cho, C.-S., Kim, M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abo2787 · Cited by 139 · see citing works
Hypoxia and the phenomenon of immune exclusion
Pietrobon, V., & Marincola, F. M. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-020-02667-4 · Cited by 119 · see citing works
Allgayer, H., Mahapatra, S., Mishra, B., Swain, B., Saha, S., Khanra, S., Kumari, K., Panda, V. K., Malhotra, D., Patil, N. S., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02338-2 · Cited by 127 · see citing works
Benchmarking and integration of methods for deconvoluting spatial transcriptomic data
Yan, L., & Sun, X. (2023) · Bioinformatics · doi:10.1093/bioinformatics/btac805 · Cited by 92 · see citing works
Lee, Y. E., Go, G.-Y., Koh, E.-Y., Yoon, H.-N., Seo, M., Hong, S.-M., Jeong, J. H., Kim, J.-C., Cho, D., Kim, T. S., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006130 · Cited by 61 · see citing works
Lin, W., Li, Y., Qiu, C., Zou, B., Gong, Y., Zhang, X., Tian, D., Sherman, W., Sanchez, F., Wu, D., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkae1298 · Cited by 46 · see citing works
Deep learning in spatial transcriptomics: Learning from the next next-generation sequencing
Heydari, A. A., & Sindi, S. S. (2023) · Biophysics Reviews · doi:10.1063/5.0091135 · Cited by 44 · see citing works
Encoding Method of Single-cell Spatial Transcriptomics Sequencing
Zhou, Y., Jia, E., Pan, M., Zhao, X., & Ge, Q. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.43887 · Cited by 32 · see citing works
Ma, C., Chitra, U., Zhang, S., & Raphael, B. J. (2022) · Cell Systems · doi:10.1016/j.cels.2022.09.002 · Cited by 27 · see citing works
Capturing the multifaceted function of adipose tissue macrophages
Matz, A. J., Qu, L., Karlinsey, K., Vella, A. T., & Zhou, B. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1148188 · Cited by 16 · see citing works
Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer
Caronni, N., Montaldo, E., Mezzanzanica, L., Cilenti, F., Genua, M., & Ostuni, R. (2021) · Immunological Reviews · doi:10.1111/imr.12944 · Cited by 6 · see citing works
An, H., Fang, W., Chen, H., Huang, W., Liu, H., Zhang, Z., Zhao, H., Zhang, Y., Zhao, M., Qiu, J., et al. (2025) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2025.108929 · Cited by 6 · see citing works
MCGAE: unraveling tumor invasion through integrated multimodal spatial transcriptomics
Yang, Y., Zhang, C., Liu, Z., Aihara, K., Zhang, C., Chen, L., & Wei, W. (2024) · Briefings in Bioinformatics · doi:10.1093/bib/bbae608 · Cited by 5 · see citing works
- Authors
- Moncada, R., Barkley, D., Wagner, F., Chiodin, M., Devlin, J. C., Baron, M., Hajdu, C. H., Simeone, D. M., & Yanai, I.
- Affiliations
- NYU Langone Health (US)
- Corresponding author
- Yanai, Itai
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2020-01-13
- Volume
- 38
- Issue
- 3
- Pages
- 333-342
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2999977864
- Cited by
- 1,045
- References
- 10
- Citations by year
- 2026: 163 · 2025: 197 · 2024: 211 · 2023: 147 · 2022: 173 · 2021: 105 · 2020: 49
- FWCI
- 39.42
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-11-23)
- Open access
- closed
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Keywords
- pancreatic ductal adenocarcinoma, spatial transcriptomics, single-cell RNA sequencing, tissue structure, tumor microenvironment, macrophages, dendritic cells, inflammatory fibroblasts, tumor cell subpopulations, cell-cell interactions
- MeSH terms
- Dendritic Cells, Humans, Macrophages, Pancreatectomy, Pancreatic Neoplasms, Gene Expression Regulation, Neoplastic, Sequence Analysis, RNA, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Carcinoma, Pancreatic Ductal, Gene Regulatory Networks, Single-Cell Analysis, Spatio-Temporal Analysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review