# The role of environmentally mediated drug resistance in facilitating the spatial distribution of residual disease

## TL;DR

This study explores how the tumor microenvironment, particularly cancer-associated fibroblasts, contributes to drug resistance and residual disease through environmental and treatment dynamics.

## Contribution

The paper introduces a hybrid-discrete-continuum model to uncover distinct mechanisms of residual disease driven by environmental and treatment factors.

## Key findings

- Two mechanisms underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue.
- Treatment breaks allow microenvironment normalization, influencing tumor eradication or survival.
- The model identifies environmental and treatment conditions that determine tumor outcomes.

## Abstract

The development of de novo resistance is a major disadvantage in molecularly targeted therapies. While much focus is on cell-intrinsic mechanisms, the microenvironment is also known to play a crucial role. This study examines interactions between cancer cells and cancer associated fibroblasts (CAFs) to understand the local crosstalk facilitating residual disease. Using a hybrid-discrete-continuum model, we explore how treatment-induced stress responses can elicit CAF activation and how breaks in treatment allow microenvironment normalisation. We investigate how fluctuating environmental conditions shape the local crosstalk and ultimately drive residual disease. Our experimentally calibrated model identifies environmental and treatment conditions that allow tumour eradication and those that enable survival. We find two distinct mechanisms that underpin residual disease: vasculature-limited drug delivery and CAF-mediated rescue. This work provides a better understanding of the mechanisms that drive the creation of localised residual disease, crucial to informing the development of more effective treatment protocols.

Mechanistic modelling of tumour-stroma crosstalk sheds light on how targeted drug dynamics and microenvironmental heterogeneity shape residual disease through distinct mechanisms in the tumour microenvironment.