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Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
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The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

Saroor A Patel1,2, Shoko Hirosue1, Paulo Rodrigues1

  • 1MRC Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK.

Nature
|June 8, 2022
PubMed

Insights

The lineage transcription factor PAX8 is essential for clear cell renal cell carcinoma (ccRCC) development. It mediates oncogenic signaling for both inherited and somatic mutations, explaining tissue-specific cancer risk.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Cancer mutations exhibit strong tissue-selectivity, but the underlying mechanisms are not fully understood.
  • Clear cell renal cell carcinoma (ccRCC) is a common kidney cancer with known genetic drivers.
  • The role of lineage transcription factors in tissue-specific cancer development is an active area of research.

Purpose of the Study:

  • To investigate the role of the lineage transcription factor paired box 8 (PAX8) in the oncogenic signaling of ccRCC.
  • To elucidate how PAX8 mediates tissue-specific cancer risk associated with genetic variants in ccRCC.
  • To understand the interplay between PAX8, VHL loss, and HIF2A in ccRCC pathogenesis.

Main Methods:

  • Experimental models
  • Functional genomics
  • Analysis of patient samples
  • Chromatin immunoprecipitation assays
  • Gene expression analysis

Main Results:

  • PAX8 is required for oncogenic signaling in ccRCC, driven by both germline variants (rs7948643) and somatic VHL inactivation.
  • Hypoxia-inducible factor 2α (HIF2A) is preferentially recruited to PAX8-bound enhancers, including the CCND1 enhancer.
  • The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding and CCND1 expression.
  • PAX8-dependent programs are co-opted for MYC expression in ccRCC metastasis.

Conclusions:

  • Lineage transcription factors like PAX8 are essential mediators of oncogenic signaling in ccRCC.
  • PAX8 plays a critical role in conferring tissue-specific cancer risk for both somatic and inherited genetic variants.
  • Understanding PAX8's role provides insights into ccRCC development and potential therapeutic strategies.

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