Spatial genomics enables multi-modal study of clonal heterogeneity in tissues

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 aberrations(1-4) as well as the makeup of the tumour microenvironment(5,6). 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.

Automated summary

The state and behavior of cells are influenced by genetic and environmental factors, particularly in the context of tumor progression where genetic aberrations and the tumor microenvironment play crucial roles. A new technology called slide-DNA-seq accurately measures genomic sequences in intact tissue sections, enabling the discovery of distinct tumor clones and their copy number alterations. This method has been applied to mouse models and primary human cancers, revealing that clonal populations are localized to specific spatial regions, and can provide valuable insights into gene expression and cellular phenotypes.