Spatial genomics enables multi-modal study of clonal heterogeneity in tissues
Name
nihms-1820300.pdf
Description
Accepted version
Size
4.73 MB
Format
Adobe PDF
Checksum (MD5)
19a4796aed6b2bf5ebdc4ead28ab14ca
Author(s)
Zhao, Tongtong
Chiang, Zachary D
Morriss, Julia W
LaFave, Lindsay M
Murray, Evan M
Del Priore, Isabella
Meli, Kevin
Lareau, Caleb A
Nadaf, Naeem M
Li, Jilong
Date Issued
2022
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Zhao, Tongtong, Chiang, Zachary D, Morriss, Julia W, LaFave, Lindsay M, Murray, Evan M et al. 2022. "Spatial genomics enables multi-modal study of clonal heterogeneity in tissues." Nature, 601 (7891).
Version
Author's final manuscript
Abstract
The state and behaviour of a cell can be influenced by both genetic and environmental factors. In particular, tumour progression is determined by underlying genetic aberrations1-4 as well as the makeup of the tumour microenvironment5,6. Quantifying the contributions of these factors requires new technologies that can accurately measure the spatial location of genomic sequence together with phenotypic readouts. Here we developed slide-DNA-seq, a method for capturing spatially resolved DNA sequences from intact tissue sections. We demonstrate that this method accurately preserves local tumour architecture and enables the de novo discovery of distinct tumour clones and their copy number alterations. We then apply slide-DNA-seq to a mouse model of metastasis and a primary human cancer, revealing that clonal populations are confined to distinct spatial regions. Moreover, through integration with spatial transcriptomics, we uncover distinct sets of genes that are associated with clone-specific genetic aberrations, the local tumour microenvironment, or both. Together, this multi-modal spatial genomics approach provides a versatile platform for quantifying how cell-intrinsic and cell-extrinsic factors contribute to gene expression, protein abundance and other cellular phenotypes.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/S41586-021-04217-4
