Challenges in Stratifying the Molecular Variability of Patient-Derived Colon Tumor Xenografts.

Magdalena Cybulska,Michalina Dabrowska,Michal Kopczynski,Malgorzata Statkiewicz,Tomasz Olesinski,Michal Mikula,Katarzyna Unrug-Bielawska,Jakub Karczmarski,Agnieszka Paziewska,Krzysztof Goryca,Aleksandra Grochowska,Marta Gajewska,Anita Tyl-Bielicka,Andrzej Mroz,Jerzy Ostrowski,Mariusz Bednarczyk,Leszek Zając,Katarzyna Paczkowska

doi:10.1155/2018/2954208

Abstract

Colorectal cancer (CRC) is the second most common cancer in Europe and a leading cause of death worldwide. Patient-derived xenograft (PDX) models maintain complex intratumoral biology and heterogeneity and therefore remain the platform of choice for translational drug discovery. In this study, we implanted 37 primary CRC tumors and five CRC cell lines into NU/J mice to develop xenograft models. Primary tumors and established xenografts were histologically assessed and surveyed for genetic variants and gene expression using a panel of 409 cancer-related genes and RNA-seq, respectively. More than half of CRC tumors (20 out of 37, 54%) developed into a PDX. Histological assessment confirmed that PDX grading, stromal components, inflammation, and budding were consistent with those of the primary tumors. DNA sequencing identified an average of 0.14 variants per gene per sample. The percentage of mutated variants in PDXs increased with successive passages, indicating a decrease in clonal heterogeneity. Gene Ontology analyses of 4180 differentially expressed transcripts (adj. p value < 0.05) revealed overrepresentation of genes involved in cell division and catabolic processes among the transcripts upregulated in PDXs; downregulated transcripts were associated with GO terms related to extracellular matrix organization, immune responses, and angiogenesis. Neither a transcriptome-based consensus molecular subtype (CMS) classifier nor three other predictors reliably matched PDX molecular subtypes with those of the primary tumors. In sum, both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution at the early phase of xenograft development, making molecular stratification of PDXs challenging.

Highlights

Patient-derived xenografts (PDXs) are established by transferring tumor tissue from patients into immunosuppressed mice
The US National Cancer Institute (NCI) is switching to PDX models from the NCI60 panel of cell lines that have been used for nearly three decades in drug discovery [2]
Most histological parameters remained stable between donor tumors and PDXs derived from them, both primary tumors and PDXs significantly differed from CLXs. Both genetic and transcriptomic profiles differed between donor tumors and PDXs, likely as a consequence of subclonal evolution of PDXs at the early phase of xenograft development

Summary

Introduction

Patient-derived xenografts (PDXs) are established by transferring tumor tissue from patients into immunosuppressed mice. PDXs are the most useful experimental models for predicting therapeutic responses and the final filters for selection of drug candidates for clinical trials and may serve as an important source of new predictive biomarkers [1]. For these reasons, the US National Cancer Institute (NCI) is switching to PDX models from the NCI60 panel of cell lines that have been used for nearly three decades in drug discovery [2]. As exemplified by a recently published study from the OncoTrack consortium [1], the use of PDXs

Methods

Results

Conclusion