Abstract C118: Transcriptome comparison of orthotopic and subcutaneous patient-derived xenografts

Abstract

Abstract Background: Patient-derived xenograft (PDX) models are used for in vivo evaluation of oncology drugs. Tumors from cancer patients are implanted into immunodeficient mice either subcutaneously or orthotopically. Subcutaneous PDX models are more prevalently used because of easy operation and monitoring, albeit increasing evidence showed that the immune microenvironment in subcutaneous tissue is different from the original tract and is therefore less patient-like. By contrast, orthotopic PDX models have the capability to metastasize and match that of the donor patient well, but resulting in extensive inflammation. Previous studies showed that tumor location may affect immune response or result in different behavior of tumor expansion in mouse models [1-4]. There is yet insufficient study on the transcriptomic difference between subcutaneous and orthotopic PDX models. Method: Tumors for 10 PDX models—including four breast, four colorectal, and two liver cancers—were used to establish pairs of subcutaneous and orthotopic models. Tumors were dissected when reaching about 1000mm3, and subjected to transcriptomic profiling by RNAseq for gene expression comparison. Results: Using traditional alignment-based RNAseq analysis, we found hundreds of genes with different expression levels between subcutaneous and orthotopic models for the three cancers. Gene ontology analysis revealed that these differentially expressed genes are highly enriched in protein translation related biological processes and pathways, such as maturation of SSU-rRNA, cap-dependent translation initiation, and peptide chain elongation. Conclusion: Subcutaneous and orthotopic PDX models differ in transcriptomes that may affect protein translation and warrant further proteomics investigations. Reference: 1, Zhang, Yong, et al. “Real–Time GFP Intravital Imaging of the Differences in Cellular and Angiogenic Behavior of Subcutaneous and Orthotopic Nude–Mouse Models of Human PC–3 Prostate Cancer.” Journal of cellular biochemistry 117.11 (2016): 2546-2551. 2, Zhao, Xianda, et al. “Tumor location impacts immune response in mouse models of colon cancer.” Oncotarget 8.33 (2017): 54775. 3, Zhang, Yi, et al. “Establishment of a murine breast tumor model by subcutaneous or orthotopic implantation.” Oncology letters 15.5 (2018): 6233-6240. 4, Nakano, Kiyotaka, et al. “Difference in morphology and interactome profiles between orthotopic and subcutaneous gastric cancer xenograft models.” Journal of toxicologic pathology 31.4 (2018): 293-300. Citation Format: xiaoqian jiang, henry li, sheng guo. Transcriptome comparison of orthotopic and subcutaneous patient-derived xenografts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C118. doi:10.1158/1535-7163.TARG-19-C118