Related Experiment Video
Updated: Aug 20, 2025
Microfluidic Co-culture of Renal Healthy and Tumor Epithelium to Model Kidney Cancer Progression
Published on: January 31, 2025
Mapping single-cell transcriptomes in the intra-tumoral and associated territories of kidney cancer
Ruoyan Li1, John R Ferdinand2, Kevin W Loudon3
1Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
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.
Insights
This study analyzed kidney tumors using single-cell transcriptomics, revealing spatial location influences CD8+ T cell exhaustion. An epithelial-mesenchymal transition program at the tumor-normal interface with IL1B macrophages presents a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Tumor behavior depends on cancer cell properties and microenvironment interactions.
- Understanding these complex cellular dependencies is crucial for effective cancer therapy.
Purpose of the Study:
- To investigate the spatial heterogeneity of kidney tumors and their microenvironment.
- To identify key cellular programs and interactions driving tumor progression.
Main Methods:
- Analysis of over 270,000 single-cell transcriptomes and 100 whole exomes from 12 kidney tumor patients.
- Utilized spatial transcriptomics for tissue validation.
- Employed de novo mutation calling from single-cell RNA-sequencing data.
Main Results:
- Tissue location of CD8+ T cell clonotypes correlates with their exhaustion state, showing intra-tumoral spatial heterogeneity.
- Inferred clonality of stromal cells and traced myeloid cell development.
- Identified six conserved meta-programs distinguishing tumor cell function.
- Found an epithelial-mesenchymal transition meta-program enriched at the tumor-normal interface co-localizing with IL1B-expressing macrophages.
Conclusions:
- Spatial location is a significant determinant of CD8+ T cell exhaustion within kidney tumors.
- The identified epithelial-mesenchymal transition program and associated macrophages represent a potential therapeutic target for kidney cancer.
