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Updated: Mar 5, 2026

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
05:36

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane

Published on: February 8, 2020

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The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Amrita M Nargund1, Can G Pham1, Yiyu Dong1

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Cell Reports
|March 23, 2017
PubMed

Insights

Clear cell renal cell carcinoma (ccRCC) development requires mutations in both VHL and PBRM1 genes. Loss of PBRM1 amplifies VHL deficiency effects, leading to kidney cancer through mTOR activation.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer subtype.
  • The VHL gene is the most frequently mutated, followed by PBRM1, in ccRCC.
  • The precise role of PBRM1 mutations in kidney cancer development remains unclear.

Purpose of the Study:

  • To investigate the biological consequences of PBRM1 mutations in kidney tumorigenesis.
  • To establish a preclinical model for studying ccRCC with PBRM1 mutations.
  • To identify molecular pathways and potential therapeutic targets in PBRM1-mutated ccRCC.

Main Methods:

  • Kidney-specific deletion of Vhl and Pbrm1 genes in a mouse model.
  • Analysis of transcriptional changes, including HIF1 and STAT3.
  • Comparative analysis of mouse and human ccRCC samples.
  • Investigation of mTOR pathway activation.

Main Results:

  • Deletion of both Vhl and Pbrm1, but not individually, led to bilateral, multifocal kidney cancers.
  • PBRM1 loss potentiated the effects of VHL deficiency on HIF1 and STAT3.
  • Both mouse and human ccRCC samples showed convergence on mTOR pathway activation.
  • A physiological preclinical model for ccRCC was successfully developed.

Conclusions:

  • Simultaneous loss of VHL and PBRM1 drives ccRCC development.
  • PBRM1 mutations cooperate with VHL inactivation to promote kidney cancer.
  • mTOR activation is a critical downstream event in PBRM1-mutated ccRCC.
  • This study provides a valuable model for investigating ccRCC and offers therapeutic insights.
Keywords:
HIF1MTORPBRM1STAT3VHLccRCCepigeneticsgeneticskidney cancermouse tumor model

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