Burge Ulukan, Ozge Saatci, Ariel Madrigal, Minjun Kim, Wensheng Tian, Mustafa Soytas, Zohreh Mehrjoo, Ozlem Sener Sahin, Kukkamadi Sreenivas, Chintada Nageswara Rao, Tamiko Nishimura, Virginie Pillon, Jean-Sebastian Anoma, Elizabeth Hill, Janusz Rak, Campbell McInnes, Morag Park, Fadi Brimo, Simon Tanguay, Ryan Charles Russell, Hamed Najafabadi, Yasser Riazalhosseini, Ozgur Sahin
Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2α 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-2α by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2α-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-2α, 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-2α G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2α in high-grade patient tumors. Together, LOX coordinates HIF-2α transcription program with TME and is a therapeutic target in ccRCC.