The state and behavior of a cell can be influenced by both genetic and environmental factors. In particular, tumor progression is determined by underlying genetic aberrations as well as the makeup of the tumor microenvironment. 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 tumor architecture and enables de novo discovery of distinct clonal lineages and their copy number alterations. We then apply slide-DNA-seq to a mouse metastasis model and a primary human cancer, revealing that cells of different clonal lineages 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 tumor microenvironment, or both. Together, this multi-modal spatial genomics approach provides a versatile platform for quantifying how cell-intrinsic and extrinsic factors contribute to gene expression, protein abundance, and other cellular phenotypes.

Figure 1, S3, S5, S6, S10mouse_cerebellum_1_dna_200114_14mouse cerebellumslide-DNA-seq
Figure S4mouse_cerebellum_1_dna_190201_21mouse cerebellumslide-DNA-seq
Figure 1, S5, S7, S9mouse_liver_met_1_dna_191114_06mouse liver metastasisslide-DNA-seq
Figure S9mouse_liver_met_1_dna_191114_05mouse liver metastasisslide-DNA-seq
Figure 2, S7, S12mouse_liver_met_2_dna_200114_10mouse liver metastasisslide-DNA-seq
Figure 2, S11mouse_liver_met_2_rna_201002_04mouse liver metastasisslide-RNA-seq v2
Figure 2, S11mouse_liver_met_2_snrna_200000_01mouse liver metastasissnRNA-seq
Figure 3, S13human_colon_cancer_3_dna_191204_19human primary colorectal cancerslide-DNA-seq
Figure 3, S13human_colon_cancer_3_scwgs_200227_01human primary colorectal cancerscWGS
Figure 3, S13human_colon_cancer_3_scwgs_210402_02human primary colorectal cancerscWGS
Figure 4, S14human_colon_cancer_4_dna_200114_13human primary colorectal cancerslide-DNA-seq
Figure 4, S14, S15human_colon_cancer_4_rna_200102_06human primary colorectal cancerslide-RNA-seq v2
N/Amouse_cerebellum_dna_4x_201027_17mouse cerebellumslide-DNA-seq 4x variant
N/Ahuman_colon_cancer_dna_4x_201027_12human primary colorectal cancerslide-DNA-seq 4x variant

*only lists figures in which in the full bead array appears, statistics for all samples can be found in Supplementary Table 2 and Extended Data Fig. 3