High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging
Abstract
Resolving the spatial distribution of RNA and protein in tissues at subcellular resolution is a challenge in the field of spatial biology. We describe spatial molecular imaging, a system that measures RNAs and proteins in intact biological samples at subcellular resolution by performing multiple cycles of nucleic acid hybridization of fluorescent molecular barcodes. We demonstrate that spatial molecular imaging has high sensitivity (one or two copies per cell) and very low error rate (0.0092 false calls per cell) and background (~0.04 counts per cell). The imaging system generates three-dimensional, super-resolution localization of analytes at ~2 million cells per sample. Cell segmentation is morphology based using antibodies, compatible with formalin-fixed, paraffin-embedded samples. We measured multiomic data (980 RNAs and 108 proteins) at subcellular resolution in formalin-fixed, paraffin-embedded tissues (nonsmall cell lung and breast cancer) and identified >18 distinct cell types, ten unique tumor microenvironments and 100 pairwise ligand-receptor interactions. Data on >800,000 single cells and ~260 million transcripts can be accessed at http://nanostring.com/CosMx-dataset .
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Combining spatial profiling and single-nucleus RNA sequencing allowed study of PDAC response to neoadjuvant therapy and revealed a treatment-refractory neural-like progenitor population that evades standard regimens.
“Similarly, the combined use of spatial profiling with single-nucleus RNA sequencing has enabled the interrogation of the response of PDAC to neoadjuvant therapy and identified a treatment-refractory “neural-like” progenitor cell type that escapes standard of care regimens279.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [279]
Spatial molecular imager resolves spatial distribution of 980 RNAs and 108 proteins in FFPE tissues at single-cell and subcellular resolution.
“Very recently, an automated and integrated platform, spatial molecular imager, was developed to resolve multi-omics spatial distribution of 980 RNAs and 108 proteins in formalin-fixed, paraffin-embedded tissues at single-cell and subcellular resolution, using a strategy similar to that of CODEX by performing multiple cycles of nucleic acid hybridization of fluorescent molecular barcodes113.”
From The technological landscape and applications of single-cell multi-omics (2023) · cites this paper as [113]
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- Authors
- He, S., Bhatt, R., Brown, C., Brown, E. A., Buhr, D. L., Chantranuvatana, K., Danaher, P., Dunaway, D., Garrison, R. G., Geiss, G., Gregory, M. T., Hoang, M. L., Khafizov, R., Killingbeck, E. E., Kim, D., Kim, T. K., Kim, Y., Klock, A., Korukonda, M., Kutchma, A., Lewis, Z. R., Liang, Y., Nelson, J. S., Ong, G. T., Perillo, E. P., Phan, J. C., Phan-Everson, T., Piazza, E., Rane, T., Reitz, Z., Rhodes, M., Rosenbloom, A., Ross, D., Sato, H., Wardhani, A. W., Williams-Wietzikoski, C. A., Wu, L., & Beechem, J. M.
- Affiliations
- Nanostring Technologies (United States) (US)
- Corresponding author
- Beechem, Joseph M.
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2022-10-06
- Volume
- 40
- Issue
- 12
- Pages
- 1794-1806
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W4302362633
- Cited by
- 814
- References
- 68
- Citations by year
- 2026: 246 · 2025: 245 · 2024: 219 · 2023: 96 · 2022: 7
- FWCI
- 47.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Biotechnology (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Funders
- NanoString Technologies
- Lam Research Corporation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Keywords
- subcellular RNA localization, protein localization, formalin-fixed paraffin-embedded tissue, nucleic acid hybridization, super-resolution localization, cell segmentation, multi-omics, tumor microenvironment, ligand-receptor interactions, non-small cell lung cancer, breast cancer, single-cell transcriptomics
- MeSH terms
- Formaldehyde, Humans, Proteins, RNA, Paraffin Embedding, Molecular Imaging
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