Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer.

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.

Cancer cell. 2022 Nov 16 [Epub ahead of print]

Ruoyan Li, John R Ferdinand, Kevin W Loudon, Georgina S Bowyer, Sean Laidlaw, Francesc Muyas, Lira Mamanova, Joana B Neves, Liam Bolt, Eirini S Fasouli, Andrew R J Lawson, Matthew D Young, Yvette Hooks, Thomas R W Oliver, Timothy M Butler, James N Armitage, Tev Aho, Antony C P Riddick, Vincent Gnanapragasam, Sarah J Welsh, Kerstin B Meyer, Anne Y Warren, Maxine G B Tran, Grant D Stewart, Isidro Cort├ęs-Ciriano, Sam Behjati, Menna R Clatworthy, Peter J Campbell, Sarah A Teichmann, Thomas J Mitchell

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., 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., European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK., 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., 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., Cambridge University Hospitals NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, 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., 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., 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: ., 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: .