Simulating non-small cell lung cancer with a multiscale agent-based model

TL;DR

This paper presents a multiscale agent-based model simulating non-small cell lung cancer, integrating molecular signaling, cellular behavior, and microenvironment interactions to better understand tumor expansion dynamics.

Contribution

It introduces a novel multiscale in silico model combining EGFR-ERK signaling with tumor microenvironment interactions, capturing feedback between molecular and cellular levels.

Findings

Increased growth factor leads to more aggressive cancer patterns.

A phase transition occurs near nutrient-rich areas, altering cell proliferation.

Extrinsic stimuli influence signaling efficiency and tumor expansion rate.

Abstract

Background The epidermal growth factor receptor (EGFR) is frequently overexpressed in many cancers, including non-small cell lung cancer (NSCLC). In silcio modeling is considered to be an increasingly promising tool to add useful insights into the dynamics of the EGFR signal transduction pathway. However, most of the previous modeling work focused on the molecular or the cellular level only, neglecting the crucial feedback between these scales as well as the interaction with the heterogeneous biochemical microenvironment. Results We developed a multiscale model for investigating expansion dynamics of NSCLC within a two-dimensional in silico microenvironment. At the molecular level, a specific EGFR-ERK intracellular signal transduction pathway was implemented. Dynamical alterations of these molecules were used to trigger phenotypic changes at the cellular level. Examining the relationship between extrinsic ligand concentrations, intrinsic molecular profiles and microscopic patterns, the results confirmed that increasing the amount of available growth factor leads to a spatially more aggressive cancer system. Moreover, for the cell closest to nutrient abundance, a phase-transition emerges where a minimal increase in extrinsic ligand abolishes the proliferative phenotype altogether. Conclusions Our in silico results indicate that, in NSCLC, in the presence of a strong extrinsic chemotactic stimulus, and depending on the cell's location, downstream EGFR-ERK signaling may be processed more efficiently, thereby yielding a migration-dominant cell phenotype and overall, an accelerated spatio-temporal expansion rate.