Genomic characterization of explant tumorgraft models derived from fresh patient tumor tissue

Abstract

BackgroundThere is resurgence within drug and biomarker development communities for the use of primary tumorgraft models as improved predictors of patient tumor response to novel therapeutic strategies. Despite perceived advantages over cell line derived xenograft models, there is limited data comparing the genotype and phenotype of tumorgrafts to the donor patient tumor, limiting the determination of molecular relevance of the tumorgraft model. This report directly compares the genomic characteristics of patient tumors and the derived tumorgraft models, including gene expression, and oncogenic mutation status.MethodsFresh tumor tissues from 182 cancer patients were implanted subcutaneously into immune-compromised mice for the development of primary patient tumorgraft models. Histological assessment was performed on both patient tumors and the resulting tumorgraft models. Somatic mutations in key oncogenes and gene expression levels of resulting tumorgrafts were compared to the matched patient tumors using the OncoCarta (Sequenom, San Diego, CA) and human gene microarray (Affymetrix, Santa Clara, CA) platforms respectively. The genomic stability of the established tumorgrafts was assessed across serial in vivo generations in a representative subset of models. The genomes of patient tumors that formed tumorgrafts were compared to those that did not to identify the possible molecular basis to successful engraftment or rejection.ResultsFresh tumor tissues from 182 cancer patients were implanted into immune-compromised mice with forty-nine tumorgraft models that have been successfully established, exhibiting strong histological and genomic fidelity to the originating patient tumors. Comparison of the transcriptomes and oncogenic mutations between the tumorgrafts and the matched patient tumors were found to be stable across four tumorgraft generations. Not only did the various tumors retain the differentiation pattern, but supporting stromal elements were preserved. Those genes down-regulated specifically in tumorgrafts were enriched in biological pathways involved in host immune response, consistent with the immune deficiency status of the host. Patient tumors that successfully formed tumorgrafts were enriched for cell signaling, cell cycle, and cytoskeleton pathways and exhibited evidence of reduced immunogenicity.ConclusionsThe preservation of the patient’s tumor genomic profile and tumor microenvironment supports the view that primary patient tumorgrafts provide a relevant model to support the translation of new therapeutic strategies and personalized medicine approaches in oncology.

KRAS Mutation Status Is Associated with Enhanced Dependency on Folate Metabolism Pathways in Non–Small Cell Lung Cancer Cells

“…Tumorgrafts typically maintain the fundamental genotypic and phenotypic features of the original tumor and have been shown to be highly predictive of patient response to therapies (35,36). Even in the limited number of tumorgrafts included in this study, initial findings are revealing.…”

Ex Vivo Testing of Patient-Derived Xenografts Mirrors the Clinical Outcome of Patients with Pancreatic Ductal Adenocarcinoma

“…Therefore, new approaches to personalized cancer therapy are necessary to match individual tumors with effective agents. Evidence from recent studies has demonstrated that tumorgrafts, or patient-derived xenografts (PDX), established by engrafting patient tumors into immunocompromised mice, preserve the structural components, heterogeneity, gene expression pattern, and genetic mutations of the original tumors (2-4). These features are maintained through several generational passages of the tumorgrafts in mice (5, 6).…”

Avatars of Personalized Cancer Therapy Can Lead to a Reduction in Head and Neck Cancer Survival Disparities

“…The failure of preclinical pipelines for therapeutic development based on mononuclear layers of tumor has led to a resurgence in the use of patient-derived tumor xenograft (PDX or tumorgrafts) models for preclinical evaluation of novel chemotherapeutic strategies [13]. Human tumorgraft models are obtained by the transplantation of primary tumor fragments straight from the operating room into an immunodeficient mouse.…”