45 Targeting Lysyl Oxidase Inhibits Tumor Progression in Clear Cell Renal Cell Carcinoma

Vollständiger Abstract

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Abstract Background Clear cell renal cell carcinoma (ccRCC) is defined by constitutive pseudohypoxia driven by von Hippel-Lindau (VHL) loss, pronounced intratumoral heterogeneity, and aberrant hypervascularity, features that collectively promote tumor progression and limit therapeutic durability. Although VEGF-targeted therapies and HIF-2α inhibitors have improved clinical outcomes, resistance frequently emerges, including mutations in the PAS-B binding pocket that impair drug efficacy. However, the mechanisms that link hypoxia-driven transcriptional programs with tumor microenvironment remodeling to sustain aggressive tumor states remain poorly defined. Methods We performed integrative single-cell transcriptomic analyses of human ccRCC tumors to resolve malignant cell heterogeneity and identify transcriptional programs associated with aggressive disease states. These analyses were complemented by immunohistochemical evaluation of patient tumor samples and functional studies in VHL-deficient ccRCC cell lines, genetically engineered models, and both cell-line-derived (CDX) and patient-derived xenografts (PDX) models. Genetic and small-molecule approaches were used to determine the role of lysyl oxidase (LOX) in tumor progression, epithelial-mesenchymal transition (EMT), angiogenesis, extracellular matrix (ECM) remodeling, metastasis, and therapeutic response. Results Single-cell analysis identified a previously unrecognized LOX-enriched malignant cell population associated with hypoxia signaling, EMT, and angiogenesis, which correlated with advanced tumor grade and poor clinical outcomes. LOX expression correlated with HIF-2α levels in patient tumors, LOX, a hypoxia-inducible gene, was selectively enriched in these aggressive states and reinforced hypoxia-associated transcriptional programs in a feedforward manner. Mechanistically, LOX sustained hypoxia-driven transcriptional activity while promoting tumor cell plasticity, EMT, angiogenesis, and metastatic potential. In parallel, LOX remodeled the tumor microenvironment by regulating ECM organization and tumor vascularization, supporting angiogenic sprouting. Targeting LOX, using both genetic silencing and pharmacologic inhibition, suppressed tumor growth, reduced collagen crosslinking, decreased vascularization, and impaired lung metastasis in vivo. LOX inhibition enhanced sensitivity to anti-angiogenic therapy and remained effective in models harboring PAS-B-mediated resistance to HIF-2α inhibitors. Combination treatment further reduced tumor burden and angiogenic signaling across multiple ccRCC models, including patient-derived xenografts. Conclusions LOX functions as a major driver of aggressive tumor states in ccRCC by linking HIF-2α-driven transcriptional programs with ECM remodeling and tumor vascularization. By sustaining tumor cell plasticity and microenvironmental support, LOX promotes disease progression and therapeutic resistance. Targeting LOX, therefore, represents a mechanistically distinct, multi-pronged therapeutic strategy to overcome resistance and improve responses to current therapies in ccRCC. DOD CDMRP Funding yes