# Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor suppressor

## TL;DR

This study shows that losing the DLC1 protein increases EMT plasticity in breast cells, which may explain its role in preventing cancer.

## Contribution

The study integrates mathematical modeling and experiments to reveal DLC1's role as a positive regulator of TGFβ-driven EMT.

## Key findings

- DLC1 loss impairs EMT progression and leads to a partial EMT phenotype.
- Losing DLC1 allows mesenchymal cells to revert to partial or epithelial states.
- DLC1 promotes EMT by enhancing SNAIL1 expression.

## Abstract

Epithelial-mesenchymal transition (EMT) plays an essential role in embryonic development, wound healing, and tumor progression. Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGFβ-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGFβ-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor.

In our study, we investigate the epithelial-mesenchymal transition (EMT), a crucial process for understanding tumor progression, metastasis, and drug resistance. EMT involves complex interactions at the RNA and protein levels, leading to significant changes in cell behavior.

We focus on the role of the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. Using breast cancer cells, we combined cellular assays with mathematical modeling to extend an existing EMT model to include DLC1. Our findings reveal that DLC1 acts as a positive regulator of EMT by promoting the expression of the transcription factor and EMT master regulator SNAIL1. When DLC1 is lost, progression of the process is impaired, and cells exhibit a partial EMT phenotype. Reversion from a completed EMT is typically impossible because cells express self-stimulatory growth factors in the mesenchymal state. Interestingly, our model also suggests that losing DLC1 in mesenchymal cells could lead to a reversion to partial or epithelial states.

Our work highlights the central role of DLC1 in cellular plasticity, underscoring its significance as a tumor suppressor. By making these findings accessible, we aim to contribute to a broader understanding of EMT and its implications for cancer research and treatment.