Phenotypic and Transcriptional Fidelity of Patient-Derived Colon Cancer Xenografts in Immune-Deficient Mice

Abstract

Xenografts of human colorectal cancer (CRC) in immune-deficient mice have great potential for accelerating the study of tumor biology and therapy. We evaluated xenografts established in NOD/scid/IL2Rγ-null mice from the primary or metastatic tumors of 27 patients with CRC to estimate their capacity for expanding tumor cells for in vitro studies and to assess how faithfully they recapitulated the transcriptional profile of their parental tumors. RNA-seq analysis of parental human CRC tumors and their derivative xenografts demonstrated that reproducible transcriptional changes characterize the human tumor to murine xenograft transition. In most but not all cases, the human stroma, vasculature, and hematopoietic elements were systematically replaced by murine analogues while the carcinoma component persisted. Once established as xenografts, human CRC cells that could be propagated by serial transplantation remained transcriptionally stable. Three histologically atypical xenografts, established from patients with peritoneal metastases, contained abundant human stromal elements and blood vessels in addition to human tumor cells. The transcriptomes of these mixed tumor/stromal xenografts did not closely resemble those of their parental tumors, and attempts to propagate such xenografts by serial transplantation were unsuccessful. Stable expression of numerous genes previously identified as high priority targets for immunotherapy was observed in most xenograft lineages. Aberrant expression in CRC cells of human genes that are normally only expressed in hematopoietic cells was also observed. Our results suggest that human CRC cells expanded in murine xenografts have great utility for studies of tumor immunobiology and targeted therapies such as immunotherapy but also identify potential limitations.

3-Dimensional Patient-Derived Lung Cancer Assays Reveal Resistance to Standards-of-Care Promoted by Stromal Cells but Sensitivity to Histone Deacetylase Inhibitors

“…The preservation of phenotype and genotype, displayed by PDX models (11), is vital to the development of new antineoplastics, not least in the age of targeted therapeutics (4,36). Similar to Perez-Soler and colleagues (9), tissue architecture was well maintained in our NSCLC samples.…”

“…Xenografts directly established from human tumors have tissue architecture and phenotype more closely resembling that of pancreatic (8), NSCLC (9,10), and colorectal (11) cancers. Expansion of patient-derived tumors in vivo can provide material at early passage for ex vivo assays, such as the clonogenic assay, which show promising correlation between drug response ex vivo and that seen in the patient (12) but is not amenable to highthroughput screening.…”

Interrogating open issues in cancer precision medicine with patient-derived xenografts

“…Athough both stromal and immune components are replaced over time by murine analogues, the haematopoietic elements show important differences in their spatial distribution 167 or may be missing overall 156,168 . This affects the signal received from molecular profiling, and could require application of specific algorithms for signal correction to avoid or reduce artefacts and biases 156,169 .…”

Patient-derived Xenografts from Colorectal Carcinoma: A Temporal and Hierarchical Study of Murine Stromal Cell Replacement

“…Prior studies (5, 7, 8, 25) suggested that the time frame for total murine stroma replacement occurs early after implantation. A study showed that the human blood vessels supporting one human CRC xenograft growth were replaced by the host murine cells by ~3 weeks post-implantation (26); another study suggested that murine endothelial cells completely supported the growth of the PDX by 30 days post-implantation (8).…”