Patient-Derived Renal Cell Carcinoma Xenografts Capture Tumor Genetic Profiles and Aggressive Behaviors

BACKGROUND: Patient-derived xenografts (PDX) have emerged as one of the most promising model systems to study cancer biology and to develop new antineoplastic drugs. Renal cell carcinoma (RCC) represents up to 90% of all kidney tumors, exhibits aggressive behavior, and has a propensity for metastasis. At diagnosis, 30% of patients with RCC have metastases, while up to 50% of those with localized disease treated with curative protocols experience recurrence. OBJECTIVE: This study aimed to establish an RCC PDX platform to identify novel clinical and molecular biomarkers of recurrence risk in order to facilitate precision medicine. METHODS: Tumor samples were obtained from surgical specimens of 87 RCC patients; fragments were implanted in immunodeficient NOD/SCID/gamma (NSG) mice. 17 Fragments were implanted subcutaneously in an initial group while a second group of 70 samples were implanted orthotopically in the subcapsular space. RESULTS: A total of 19 PDX developed only after orthotopic implantation, and included 15 cases of clear cell RCC subtype, 3 cases of papillary subtype, and 1 unclassifiable tumor. 1 PDX of clear cell RCC recapitulated the phenotype of vena caval tumor thrombus extension that had been diagnosed in the source patient. PDX characterization by immunohistochemistry and targeted sequencing indicated that all PDXs preserved RCC identity and major molecular alterations. Moreover, the capacity of tumor engraftment was a strong prognostic indicator for patients with locally advanced disease. CONCLUSION: Taken together, these results suggest that the orthotopic xenograft model of RCC represents a suitable tool to study RCC biology, identify biomarkers, and to test therapeutic candidates.

Automated summary

This study aimed to establish a renal cell carcinoma (RCC) patient-derived xenograft (PDX) platform to identify novel clinical and molecular biomarkers of recurrence risk. Orthotopic implantation was found to be more suitable for establishing the PDX model, preserving RCC identity and major molecular alterations. The capacity of tumor engraftment was also found to be a strong prognostic indicator for patients with locally advanced disease.