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a, Schematic of the screen. DTCs interact with hepatocytes harbouring seeding-promoting or seeding-suppressing perturbations, influencing local metastatic outgrowth and therefore sgRNA enrichment in metastasis-proximal hepatocytes. b, Genes ranked by proximal enrichment score. Seeding-promoting factors are enriched in GFP+mCherry+ hepatocytes (red). Suppressing factors are enriched in GFP+mCherry− hepatocytes (green). Top-scoring SRFs are listed on the right. c, The log-transformed fold change (FC) of individual sgRNAs (vertical lines) for two suppressing and two promoting factors across all mice (n = 7) and library batches (n = 3). d, GSEA of SRFs. The dot size indicates the gene set size. e, Interaction analysis in a human CRC liver metastasis. 22 SRFs expressed by metastasis-proximal hepatocytes (orange) are predicted to interact with LRs on tumour cells at the metastatic leading edge (turquoise). f, Predicted interactions between SRFs and LRs that are frequently mutated in liver metastases. CNV status is shown in orange (amplified), yellow (mutation) or blue (deleted). g, Representative fluorescence micrograph showing co-culture of Alb-cre;dCas9-SPH hepatocytes overexpressing SRFs (GFP+) and AKPSsLP-mCherry colonies (mCherry+, arrowheads). Scale bar, 100 μm. h–k, The CFU per well of AKPSsLP-mCherry organoids co-cultured with AML12dCas9-SPH cells overexpressing SRFs (n = 3 wells; h), AKPSsLP-mCherry organoids co-cultured with AML12 cells overexpressing Plxnb2 (n = 10 wells; i), AKPSsLP-mCherry organoids treated with rmPlexin B2 (n = 3 wells; j) and PDOs treated with rhPlexin B2 (n = 5 wells; k). Statistical analysis was performed using ordinary one-way analysis of variance (ANOVA) with Dunnet’s correction for multiple testing (h–j) or two-tailed unpaired t-tests (k). Data are mean ± s.d. For b–d, results are pooled from three independent experiments.