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Long-Read Spatial Transcriptomics of Patient-Derived Clear Cell Renal Cell Carcinoma Organoids Identifies

Hazem Abdullah1, Ying Zhang1, Kathryn Kirkwood2

  • 1School of Medicine, University of St Andrews, North Haugh, St Andrews KY16 9TF, UK.

Cancers
|January 28, 2026
PubMed
Abstract

Insights

Patient-derived organoids and spatial transcriptomics reveal clear cell renal cell carcinoma (ccRCC) heterogeneity. This approach maps gene expression changes and treatment responses within the tumor microenvironment.

Area of Science:

  • Oncology
  • Genomics
  • Cancer Research

Background:

  • Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype, characterized by significant intra-tumoural heterogeneity complicating treatment.
  • Patient-derived organoids (PDOs) provide a physiologically relevant model to study ccRCC diversity and treatment efficacy.
  • Integrating PDOs with spatial transcriptomics allows for mapping spatially resolved transcriptional and isoform-level changes within the tumour microenvironment.

Purpose of the Study:

  • To establish a robust workflow for generating patient-derived ccRCC organoids that retain original tumour components.
  • To investigate the spatial heterogeneity of ccRCC using these organoids combined with spatial transcriptomics.
  • To analyze the transcriptional and isoform-level responses to novel therapeutics within the tumour microenvironment.

Main Methods:

  • Development of a workflow for generating patient-derived ccRCC organoids without passaging, preserving original cellular components (cancer, stromal, immune).
  • Application of long-read spatial transcriptomics to profile organoids, identifying transcriptionally distinct regions.
  • Isoform-level analysis to detect spatially variable gene expression, including glutaminase (GLS) isoforms.

Main Results:

  • Spatial transcriptomic profiling revealed significant transcriptional heterogeneity within and across ccRCC organoids.
  • Spatially variable expression of glutaminase (GLS) isoforms (GAC and KGA) was identified with heterogeneous distributions.
  • Treatment with NUC-7738 induced substantial transcriptional remodelling in organoids, affecting ribosomal and mitochondrial gene expression.

Conclusions:

  • The combination of long-read spatial transcriptomics and PDOs is a powerful, scalable method for dissecting ccRCC heterogeneity.
  • This approach enables the elucidation of spatially resolved transcriptional and isoform-level responses to novel therapeutics.
  • This methodology advances the understanding of ccRCC tumour microenvironment and therapeutic interventions.
Keywords:
NUC-7738clear cell renal cell carcinomaheterogeneitylong read sequencingorganoid spatial transcriptomicspatient-derived organoidstranscript isoforms

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