PMID- 36423636 OWN - NLM STAT- MEDLINE VI - 40 IP - 12 TI - Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer. PG - 1583-1599.e10 CI - Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cancer Cell JT - Cancer cell JID - 101130617 IS - 1878-3686 (Electronic) LID - S1535-6108(22)00548-7 [pii] LID - 10.1016/j.ccell.2022.11.001 [doi] FAU - Li, Ruoyan AU - Li R AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Ferdinand, John R AU - Ferdinand JR AD - Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. FAU - Loudon, Kevin W AU - Loudon KW AD - Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Bowyer, Georgina S AU - Bowyer GS AD - Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. FAU - Laidlaw, Sean AU - Laidlaw S AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Muyas, Francesc AU - Muyas F AD - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Mamanova, Lira AU - Mamanova L AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Neves, Joana B AU - Neves JB AD - UCL Division of Surgery and Interventional Science, Royal Free Hospital, London NW3 2PS, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London NW3 2PS, UK. FAU - Bolt, Liam AU - Bolt L AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Fasouli, Eirini S AU - Fasouli ES AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Lawson, Andrew R J AU - Lawson ARJ AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Young, Matthew D AU - Young MD AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Hooks, Yvette AU - Hooks Y AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Oliver, Thomas R W AU - Oliver TRW AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Butler, Timothy M AU - Butler TM AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Armitage, James N AU - Armitage JN AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Aho, Tev AU - Aho T AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Riddick, Antony C P AU - Riddick ACP AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Gnanapragasam, Vincent AU - Gnanapragasam V AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK. FAU - Welsh, Sarah J AU - Welsh SJ AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Meyer, Kerstin B AU - Meyer KB AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Warren, Anne Y AU - Warren AY AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Tran, Maxine G B AU - Tran MGB AD - UCL Division of Surgery and Interventional Science, Royal Free Hospital, London NW3 2PS, UK; Specialist Centre for Kidney Cancer, Royal Free Hospital, London NW3 2PS, UK. FAU - Stewart, Grant D AU - Stewart GD AD - Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK. FAU - Cortés-Ciriano, Isidro AU - Cortés-Ciriano I AD - European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Behjati, Sam AU - Behjati S AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Clatworthy, Menna R AU - Clatworthy MR AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK. FAU - Campbell, Peter J AU - Campbell PJ AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK. FAU - Teichmann, Sarah A AU - Teichmann SA AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Department of Physics, Cavendish Laboratory, JJ Thomson Avenue, Cambridge CB3 0HE, UK. Electronic address: st9@sanger.ac.uk. FAU - Mitchell, Thomas J AU - Mitchell TJ AD - Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK; Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK; Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: tjm@sanger.ac.uk. IS - 1535-6108 (Linking) SB - IM MH - Humans MH - Transcriptome MH - Gene Expression Profiling MH - *Carcinoma, Renal Cell/genetics MH - *Kidney Neoplasms/genetics MH - Epithelial-Mesenchymal Transition MH - Tumor Microenvironment/genetics MH - Single-Cell Analysis OTO - NOTNLM OT - IL1B OT - kidney cancer OT - multi-regional sequencing OT - pseudocapsule OT - renal cell carcinoma OT - single-cell sequencing OT - tumor microenvironment PMC - PMC9767677 DCOM- 20221215 LR - 20240210 DP - 20221212 DEP - 20221123 AB - Tumor behavior is intricately dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. To understand these dependencies within the wider microenvironment, we studied over 270,000 single-cell transcriptomes and 100 microdissected whole exomes from 12 patients with kidney tumors, prior to validation using spatial transcriptomics. Tissues were sampled from multiple regions of the tumor core, the tumor-normal interface, normal surrounding tissues, and peripheral blood. We find that the tissue-type location of CD8+ T cell clonotypes largely defines their exhaustion state with intra-tumoral spatial heterogeneity that is not well explained by somatic heterogeneity. De novo mutation calling from single-cell RNA-sequencing data allows us to broadly infer the clonality of stromal cells and lineage-trace myeloid cell development. We report six conserved meta-programs that distinguish tumor cell function, and find an epithelial-mesenchymal transition meta-program highly enriched at the tumor-normal interface that co-localizes with IL1B-expressing macrophages, offering a potential therapeutic target.