A patient-derived ccRCC model that retains native stromal features to assess fibrosis-driven personalized therapeutic response
Clear cell renal cell carcinoma (ccRCC) is characterized by a complex tumor microenvironment, in which stromal components such as collagen and cancer- associated fibroblasts (CAF) play a pivotal role in therapeutic resistance. To investigate the contribution of fibrosis to interpatient variability in treatment response, we developed a patient-derived xenograft (PDX) model using the chick chorioallantoic membrane (CAM) assay. This model preserves key stromal features of the original tumors, including collagen types I, III and VII, fibronectin, lysyl oxidases (LOX), and CAF markers such as fibroblast activation protein (FAP) and a-smooth muscle actin (a-SMA). Transcriptomic analyses confirm the conservation of gene expression profiles related to stromal architecture, extracellular matrix composition, and cellular metabolism within the xenografts. In vivo assays across multiple PDXs reveal heterogeneous responses to antifibrotic agents, which correlate with the collagen content of the original tumors. Notably, antifibrotic pretreatment enhances therapeutic efficacy in xenografts derived from tumors with collagen levels ranging from 5 to 25%. This model provides a physiologically relevant platform to assess fibrosis- driven therapeutic responses in ccRCC and supports the integration of stromal profiling into personalized treatment strategies. Overall design: RNA-seq profiling of original human ccRCC tumors and associated patient-derived xenografts cultivated on the chorioallantoic membrane of chick embryos for 7 days.