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Conserved patterns of transcriptional dysregulation, heterogeneity, and cell states in clear cell kidney cancer

Olivia Lombardi1, Ran Li1, Faiz Jabbar1

  • 1NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK.

Cell Reports
|January 10, 2025
PubMed

Insights

Single-cell transcriptomics reveals conserved transcriptional patterns in clear cell kidney cancer. These patterns, linked to tumor progression and metastasis, arise from cell lineage plasticity rather than genetic heterogeneity.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Clear cell kidney cancer exhibits genetic heterogeneity and driver events influencing progression and therapy resistance.
  • Understanding transcriptional programs in cancer and stromal cells is crucial for novel therapeutic strategies.

Purpose of the Study:

  • To investigate transcriptional programs in kidney tumors and normal kidney tissue using single-cell transcriptomics.
  • To identify conserved transcriptional dysregulation patterns and their upstream regulators.
  • To explore the link between transcriptional heterogeneity, genetic alterations, and clinical outcomes.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) was performed on 75 multi-regional biopsies from kidney tumors and adjacent normal kidney tissue.
  • Bioinformatic analyses were used to identify transcriptional patterns, dysregulation, and upstream regulators.
  • Correlation of transcriptional states with genetic alterations (e.g., Chr14q loss) and clinical data was performed.

Main Results:

  • Conserved patterns of transcriptional dysregulation and their regulators were identified in tumor and vascular components.
  • Subclonal transcriptional consequences of Chr14q loss associated with metastatic potential were described.
  • Prognostically significant intratumor transcriptional heterogeneity was identified, reflecting co-existing cell states.
  • These heterogeneous cell states were found to be a consequence of lineage plasticity, not solely genetic heterogeneity.

Conclusions:

  • Single-cell transcriptomics provides insights into the complex transcriptional landscape of clear cell kidney cancer.
  • Transcriptional dysregulation and heterogeneity are key features driving tumor progression and metastasis.
  • Lineage plasticity plays a significant role in generating observed intratumor transcriptional heterogeneity.
  • Understanding these transcriptional programs may lead to new therapeutic approaches for kidney cancer.
Keywords:
CP: CancerCP: GenomicsHIFVHLaneuploidyccRCCevolutionheterogeneityhypoxiaplasticitysingle-celltranscriptomics

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