Summary
Anti-angiogenic therapies (AATs) exhibit limited efficacy, as most cancer patients inevitably develop resistance to them. In this study, data generated using a nasopharyngeal carcinoma orthotopic mouse model, combined with clinical data, reveal compensatory vasculogenic mimicry (VM) formation during AATs treatment and the association of VM with poor prognosis in nasopharyngeal carcinoma. Additionally, data-independent acquisition mass spectrometry-based proteomics show that upregulation of ADAM10 contributes to VM. Mechanistically, epigenetic and high-resolution chromatin interaction landscape analyses demonstrate that although ADAM10 does not interact with either the proximal or distal enhancers, DDX5, a transcription factor of ADAM10, is regulated by long-range looping enhancer-promoter interactions. Further analyses identify transcription factors binding to critical constituents of the DDX5 super-enhancer. Ingenol Mebutate, which docks excellently with DDX5, reverses ADAM10-mediated gene expression changes, thereby effectively suppressing compensatory VM formation and metastasis and improving prognosis. Collectively, these findings provide insights into the clinical application of AATs.
Statement of Significance: Our findings strongly suggest that compensatory VM formation contributes to resistance to AADs; co-treatment with small molecules targeting compensatory VM formation and AADs may enhance the inhibition of compensatory VM formation and improve prognosis.