Integration of transcriptomics data into agent-based models of solid tumor metastasis

Abstract

Recent progress in our understanding of cancer mostly relies on the systematic profiling of patient samples with high-throughput techniques like transcriptomics. With this approach, one can find gene signatures and networks underlying cancer aggressiveness and therapy resistance. However, omics data alone cannot generate insights into the spatiotemporal aspects of tumor progression. Here, multi-level computational modeling is a promising approach that would benefit from protocols to integrate the data generated by the high-throughput profiling of patient samples. We present a computational workflow to integrate transcriptomics data from tumor patients into hybrid, multi-scale cancer models. In the method, we conduct transcriptomics analysis to select key differentially regulated pathways in therapy responders and non-responders and link them to agent-based model parameters. We then determine global and local sensitivity through systematic model simulations that assess the relevance of parameter variations in triggering therapy resistance. We illustrate the methodology with a de novo generated agent-based model accounting for the interplay between tumor and immune cells in a melanoma micrometastasis. The application of the workflow identifies three distinct scenarios of therapy resistance.

Keywords

• Systems biology
• Multi-scale modelling
• Melanoma
• Immunotherapy