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Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment
Biorxiv : the Preprint Server for Biology
|August 12, 2026
Summary
Lysyl oxidase (LOX) drives clear cell renal cell carcinoma (ccRCC) by stabilizing HIF-2α and remodeling the tumor microenvironment. Inhibiting LOX suppresses tumor growth and enhances therapy response in ccRCC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Clear cell renal cell carcinoma (ccRCC) progression is linked to sustained hypoxia-inducible factor 2-alpha (HIF-2α) transcription.
- The molecular mechanisms maintaining this HIF-2α program after VHL loss are not fully understood.
Purpose of the Study:
- To identify molecular mediators sustaining the HIF-2α transcription program in ccRCC.
- To investigate the role of lysyl oxidase (LOX) as a potential therapeutic target in ccRCC.
Main Methods:
- Single-cell transcriptomics to identify key drivers in ccRCC.
- In vitro and in vivo experiments using genetic and pharmacological inhibition of LOX.
- Assessment of LOX's impact on HIF-2α stability, extracellular matrix (ECM) remodeling, angiogenesis, and tumor progression.
- Evaluation of LOX inhibition in combination with anti-angiogenic therapy and in belzutifan-resistant models.
Main Results:
- Lysyl oxidase (LOX) was identified as a driver of ccRCC progression, associated with hypoxia/EMT gene programs and poor outcomes.
- LOX stabilizes HIF-2α by inhibiting its degradation and promotes tumor growth, metastasis, and angiogenesis by remodeling the ECM.
- Inhibition of LOX destabilizes HIF-2α, disrupts ECM, reduces angiogenesis, and suppresses tumor initiation, growth, and metastasis.
- LOX inhibition improved response to anti-angiogenic therapy and was effective in belzutifan-resistant ccRCC models.
- Nuclear LOX protein levels correlated with nuclear HIF-2α in high-grade ccRCC tumors.
Conclusions:
- Lysyl oxidase (LOX) is a crucial coordinator of the HIF-2α transcription program and the tumor microenvironment (TME) in ccRCC.
- LOX represents a promising therapeutic target for ccRCC, with potential to overcome resistance to existing therapies.
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