The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Abstract

Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

Preclinical models of pancreatic ductal adenocarcinoma: challenges and opportunities in the era of precision medicine

“…These changes are deeply rooted in the subtle drift of the genetic landscape. Dynamic changes causing various genomic instabilities are documented during PDX passaging [9], including copy number alteration (CNA), which is associated with tumor progression [42]. Monitoring 1110 PDX models across 24 tumor types [43] revealed model-acquired an average of 12.3% CNA in the genome within four passages.…”

“…Selection pressure is established not only because of intratumoral competition for maximum expansion speed but also because of adaptation to the culture environment. In addition, selection bias randomly resets the subclone constitution between successive passages [9] (Fig. 1).…”

“…Third, stroma replacement with host components results in genetic and functional drift from the primary tumor [82]. Later passages were found to be more sensitive to pharmacological treatment [9]. Fourth, PDX models are difficult to genetically manipulate.…”

“…These issues are usually underrepresented in model construction. Moreover, subclonal divergence from the primary tumor is introduced through serial passages [9], which is an indispensable process for in vitro culture and xenograft models (Fig. 1).…”

Humanized Mice as an Effective Evaluation System for Peptide Vaccines and Immune Checkpoint Inhibitors

“…Consequently, the established patient-derived xenograft (PDX) system, which transplants a patient's cancer tissues (minimal standard was reported by Meehan et al [131]), combined with a patient's T cells, is widely accepted. The detail was intensively reviewed by other researchers [132][133][134].…”