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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Li, Ruoyan 
Ferdinand, John R 
Loudon, Kevin W 
Bowyer, Georgina S 
Laidlaw, Sean 

Abstract

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.

Description

Keywords

IL1B, kidney cancer, multi-regional sequencing, pseudocapsule, renal cell carcinoma, single-cell sequencing, tumor microenvironment, Humans, Transcriptome, Gene Expression Profiling, Carcinoma, Renal Cell, Kidney Neoplasms, Epithelial-Mesenchymal Transition, Tumor Microenvironment, Single-Cell Analysis

Journal Title

Cancer Cell

Conference Name

Journal ISSN

1535-6108
1878-3686

Volume Title

40

Publisher

Elsevier BV
Sponsorship
Kidney Research UK (TF_013_20171124)
Medical Research Council (MR/S035842/1)
Cancer Research UK (C96/A25177)
Cancer Research UK (27176)