2. Academic Validation
  3. Conserved patterns of transcriptional dysregulation, heterogeneity, and cell states in clear cell kidney cancer

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

  • Cell Rep. 2025 Jan 28;44(1):115169. doi: 10.1016/j.celrep.2024.115169.
Olivia Lombardi 1,  Ran Li 1,  Faiz Jabbar 1,  Hannah Evans 1,  Silvia Halim 1,  Joanna D C C Lima 2,  Lisa Browning 3,  Helen M Byrne 4,  Hani Choudhry 5,  Peter J Ratcliffe 6,  David R Mole 7
Affiliations

Affiliations

  • 1 NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK.
  • 2 NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK; Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ, UK.
  • 3 Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Headington, Oxford OX3 9DU, UK.
  • 4 Wolfson Centre for Mathematical Biology, Mathematical Institute, University of Oxford, Oxford OX2 6GG, UK; Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ, UK.
  • 5 Department of Biochemistry, Faculty of Science, Center of Innovation in Personalized Medicine, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah 3270, Saudi Arabia.
  • 6 Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Headington, Oxford OX3 7DQ, UK; The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 7 NDM Research Building, University of Oxford, Old Road Campus, Headington, Oxford OX3 7FZ, UK. Electronic address: david.mole@ndm.ox.ac.uk.
PMID: 39792555 DOI: 10.1016/j.celrep.2024.115169
Abstract

Clear cell kidney cancers are characterized both by conserved oncogenic driver events and by marked intratumor genetic and phenotypic heterogeneity, which help drive tumor progression, metastasis, and resistance to therapy. How these are reflected in transcriptional programs within the Cancer and stromal cell components remains an important question with the potential to drive novel therapeutic approaches to treating Cancer. To better understand these programs, we perform single-cell transcriptomics on 75 multi-regional biopsies from kidney tumors and normal kidney. We identify conserved patterns of transcriptional dysregulation and their upstream regulators within the tumor and associated vasculature. We describe recurrent subclonal transcriptional consequences of Chr14q loss linked to metastatic potential. We identify prognostically significant conserved patterns of intratumor transcriptional heterogeneity. These reflect co-existing cell states found in both Cancer cells and normal kidney cells, indicating that rather than arising from genetic heterogeneity they are a consequence of lineage plasticity.

Keywords

CP: Cancer; CP: Genomics; HIF; VHL; aneuploidy; ccRCC; evolution; heterogeneity; hypoxia; plasticity; single-cell; transcriptomics.

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