Kidney cancer PDOXs reveal patient-specific pro-malignant effects of antiangiogenics and its molecular traits

Area of Science:

• Oncology
• Cancer Biology
• Translational Medicine

Background:

• Antiangiogenic therapies are widely used for renal cell carcinoma (RCC).
• Their impact on tumor invasiveness and metastasis remains a critical, debated topic.
• Patient heterogeneity necessitates models reflecting diverse treatment responses.

Purpose of the Study:

• To investigate the heterogeneous effects of antiangiogenic therapies on tumor invasiveness and metastasis.
• To identify molecular biomarkers predicting treatment response in renal cell carcinoma.
• To develop patient-derived xenograft models for studying inter-patient heterogeneity.

Main Methods:

• Development of 27 patient biopsy-derived orthotopic xenograft models (Ren-PDOX) for renal cell carcinoma.
• Species-discriminative RNA sequencing to analyze tumor cell-specific gene expression.
• Gene filtering using invasion-annotated patient data to identify candidate biomarkers.
• Validation of candidate biomarkers in an independent cohort of 15 antiangiogenic-treated patients.

Main Results:

• Antiangiogenic treatment led to increased invasiveness and metastasis in some Ren-PDOX models, while others showed no change.
• A tumor cell-specific differential gene expression profile was identified, correlating with tumor progression and aggressivity in TCGA RCC patients.
• ALDH1A3 was pinpointed as a key gene differentiating pro-invasive subtypes in Ren-PDOX models.
• Pre-treatment ALDH1A3 levels significantly predicted a pro-aggressive response in patients receiving antiangiogenic therapy.

Conclusions:

• The effects of antiangiogenic drugs on tumor invasion and metastasis are heterogeneous and can promote malignancy.
• ALDH1A3 serves as a potential molecular biomarker for selecting patients who will benefit most from antiangiogenic treatment.
• These findings highlight the importance of personalized medicine approaches in cancer therapy.