Comparative RNA-Seq Analysis Revealed Tissue-Specific Splicing Variations during the Generation of the PDX Model

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Tissue-specific gene expression dictates organ function and tumor characteristics.
• Understanding how tissue specificity is maintained in patient-derived xenografts (PDX) is crucial for cancer research.
• Immune-compromised mouse models are widely used for preclinical cancer studies.

Purpose of the Study:

• To compare gene expression and splicing patterns between primary tumors and their corresponding patient-derived xenografts (PDX).
• To assess the conservation of tissue-specific gene expression in PDX models.
• To identify alterations in RNA splicing during the formation of PDX tumors.

Main Methods:

• Comparative RNA-sequencing (RNA-seq) analysis of four primary-PDX tumor pairs.
• Analysis of RNA biotype distribution and splicing patterns.
• Correlation analysis of tissue-specific genes.
• Splicing variant-specific RT-PCR validation.

Main Results:

• Conserved RNA biotype distribution was observed between primary tumors and PDX.
• Significant changes in splicing patterns, primarily skipped exons, were detected in PDX tumors.
• Strong positive correlations in tissue-specific gene expression were found between primary and PDX pairs, except for gastric cancer.
• Gastric cancer PDX models showed an inverse correlation in tissue-specific gene expression.

Conclusions:

• PDX formation can lead to tissue-specific alterations in splicing events.
• Splicing changes represent a variable factor affecting the integrity of primary-PDX relationships.
• These findings highlight the importance of considering splicing alterations when interpreting PDX model data.