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Single-cell analyses have revealed extensive heterogeneity between and within human tumours(1-4), but complex single-cell phenotypes and their spatial context are not at present reflected in the histological stratification that is the foundation of many clinical decisions. Here we use imaging mass cytometry(5) to simultaneously quantify 35 biomarkers, resulting in 720 high-dimensional pathology images of tumour tissue from 352 patients with breast cancer, with long-term survival data available for 281 patients. Spatially resolved, single-cell analysis identified the phenotypes of tumour and stromal single cells, their organization and their heterogeneity, and enabled the cellular architecture of breast cancer tissue to be characterized on the basis of cellular composition and tissue organization. Our analysis reveals multicellular features of the tumour microenvironment and novel subgroups of breast cancer that are associated with distinct clinical outcomes. Thus, spatially resolved, single-cell analysis can characterize intratumour phenotypic heterogeneity in a disease-relevant manner, with the potential to inform patient-specific diagnosis.

A single-cell, spatially resolved analysis of breast cancer demonstrates the heterogeneity of tumour and stroma tissue and provides a more-detailed method of patient classification than the current histology-based system.

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations(1-7). However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the proapoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice(8-11), and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

A method termed ac(4)C-seq is introduced for the transcriptome-wide mapping of the RNA modificationN(4)-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.

N-4-acetylcytidine (ac(4)C) is an ancient and highly conserved RNA modification that is present on tRNA and rRNA and has recently been investigated in eukaryotic mRNA(1-3). However, the distribution, dynamics and functions of cytidine acetylation have yet to be fully elucidated. Here we report ac(4)C-seq, a chemical genomic method for the transcriptome-wide quantitative mapping of ac(4)C at single-nucleotide resolution. In human and yeast mRNAs, ac(4)C sites are not detected but can be induced-at a conserved sequence motif-via the ectopic overexpression of eukaryotic acetyltransferase complexes. By contrast, cross-evolutionary profiling revealed unprecedented levels of ac(4)C across hundreds of residues in rRNA, tRNA, non-coding RNA and mRNA from hyperthermophilic archaea. (AcC)-C-4 is markedly induced in response to increases in temperature, and acetyltransferase-deficient archaeal strains exhibit temperature-dependent growth defects. Visualization of wild-type and acetyltransferase-deficient archaeal ribosomes by cryo-electron microscopy provided structural insights into the temperature-dependent distribution of ac(4)C and its potential thermoadaptive role. Our studies quantitatively define the ac(4)C landscape, providing a technical and conceptual foundation for elucidating the role of this modification in biology and disease(4-6).