Patient-derived xenografts undergo mouse-specific tumor evolution

Area of Science:

• Oncology
• Genomics
• Cancer Research

Background:

• Patient-derived xenografts (PDXs) are widely used cancer models, assumed to mirror primary tumor genomics.
• Understanding genomic alterations in PDXs is vital for their reliable application in research.

Purpose of the Study:

• To investigate the dynamics of copy number alterations (CNAs) in a large cohort of patient-derived xenografts (PDXs).
• To compare CNA acquisition in PDXs with genomic evolution in human tumors.
• To assess the relationship between PDX genomic stability and drug response.

Main Methods:

• Analysis of copy number alterations (CNAs) across 1,110 PDX samples from 24 cancer types.
• Monitoring CNA dynamics during serial PDX passaging.
• Correlation analysis between PDX CNAs, primary tumor characteristics, and drug response data.

Main Results:

• Rapid accumulation of CNAs was observed during PDX passaging, often driven by selection of minor clones.
• CNA acquisition in PDXs correlated with primary tumor aneuploidy and heterogeneity but differed in specific events.
• Several common human tumor CNAs were lost during PDX propagation.
• PDX genomic stability was linked to chemotherapy and targeted drug response.

Conclusions:

• PDX models undergo significant genomic changes, particularly in CNAs, that diverge from human tumor evolution.
• These genomic shifts in PDXs can influence their response to cancer therapies.
• Careful consideration of PDX genomic dynamics is essential for accurate preclinical cancer modeling.