Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment
Ulukan, B.; Saatci, O.; Madrigal, A.; Kim, M.; Tian, W.; Soytas, M.; Mehrjoo, Z.; Sahin, O. S.; Sreenivas, K.; Rao, C. N.; Nishimura, T.; Pillon, V.; Anoma, J.-S.; Hill, E.; Rak, J.; McInnes, C.; Park, M.; Brimo, F.; Tanguay, S.; Russell, R. C.; Najafabadi, H. S.; Riazalhosseini, Y.; Sahin, O.
Show abstract
Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.
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