Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts
Résumé
Cancer is as unique as the person fighting it. With exception of few biomarker-driven therapies, patients go through rounds of trialand-error approaches to find the best treatment. Using patientderived cell lines, we show that zebrafish-larvae-xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intra-tumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI than to FOLFOX, not only between isogenic tumors but also within the same tumor. We directly compared zebrafish-xenografts with mouse-xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrates how KRAS mutations can provide proliferation advantages in relation to KRAS WT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish-xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish Patient Derived Xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemo and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish-larvae-xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.
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