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VHL Gene Restoration Supports RCC Reprogramming to iPSCs but Does Not Ensure Line Stability.

Zsuzsanna Lichner1,2, Yasaman Shamshirgaran3, Katarzyna Pieczonka4,5

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Reprogramming clear cell renal cell carcinoma (ccRCC) cells to stem cells is challenging. While restoring the VHL gene aids reprogramming, other genetic mutations in ccRCC may prevent stable pluripotency.

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Area of Science:

  • Cancer Biology
  • Stem Cell Biology
  • Regenerative Medicine

Background:

  • Modeling precancerous stages aids understanding early cancer transformation.
  • Cancer hijacks developmental pathways, suggesting reprogramming could model precancer.
  • Organoid models offer potential for personalized, targeted cancer therapies.

Purpose of the Study:

  • To model precancerous clear cell renal cell carcinoma (ccRCC) by reprogramming cancer cells.
  • To investigate the role of the von Hippel-Lindau (VHL) gene in ccRCC reprogramming.
  • To assess the potential of organoid models for studying early cancer development.

Main Methods:

  • Attempted reprogramming of patient-derived ccRCC and normal renal epithelial cell lines.
  • Utilized lentivirus or episomal reprogramming vectors for cellular reprogramming.
  • Re-expressed the VHL gene in ccRCC cells to assess its impact on reprogramming efficiency.

Main Results:

  • Normal renal cells reprogrammed efficiently, while ccRCC cells failed.
  • Re-expressing VHL restored epithelial phenotype and oxidative metabolism in ccRCC cells but did not enable stable reprogramming.
  • VHL-corrected ccRCC cells generated NANOG+ cells but remained dependent on reprogramming factors.

Conclusions:

  • VHL expression is necessary but insufficient for stable cellular reprogramming of ccRCC cells.
  • Additional genetic lesions in ccRCC cells likely prevent the stabilization of the pluripotent state.
  • Further research is needed to overcome reprogramming barriers in ccRCC for effective modeling.