Impact of orthotopic versus subcutaneous implantation on patient-derived xenograft transcriptomic profile

Background: Patient-derived xenografts (PDXs) have become the leading model system in oncology drug discovery. Depending on their site of implantation, PDX models from solid tumors can be divided into two categories: subcutaneous (s.c.) and orthotopic (ortho). The advantage s.c. implantation is that tumor size easily monitored, allowing fast validation efficacy. However, since microenvironment likely different tissue origin for most types, there concern PDXs may not fully recapitulate complexities human cancer. Understanding how impacts transcriptome essential selecting suitable an study. In this study 49 ortho/s.c. pairs five cancer types were analyzed. Methods: Cryopreserved or fresh tissues (∼2–3 mm diameter) transplanted NOD/SCID BALB/c nude mice. total, RNA-seq data was obtained 98 samples (49 pairs) including breast, colorectal, gastric, liver, pancreatic. Sequencing reads aligned to both mouse reference genomes species each read assigned based which alignment yielded fewer mismatches. Following post-alignment quality control transcript integrity, abundance quantified using Kallisto software tool. Paired comparisons between ortho carried out R package sleuth. Results: Overall, gene expression profiles highly similar matched pairs, with a median gene-wise Spearman correlation coefficient 0.85. Using <0.05 cut-off false discovery rate, 211 differentially expressed genes identified. For these genes, magnitude change less than two-fold. Gene set enrichment analysis suggested sets related extracellular matrix functions significantly enriched top-ranked genes. Considering pooled analysis, results represent common patterns across examined separate preliminary additional impacted by type-specific manner. Conclusions: Although transcriptomes similar, subtle differences identified prove relevant certain scenarios, especially if experimental targets molecule involved one pathways site. Aside mechanism action, also suggest choice whether use should depend type interest. No conflict