# The atypical KRAS Q22K mutation directs TGF‐β response towards partial epithelial‐to‐mesenchymal transition in patient‐derived colorectal cancer tumoroids

## TL;DR

The study shows that the KRAS Q22K mutation in colorectal cancer tumoroids causes a partial epithelial-to-mesenchymal transition in response to TGF-β, promoting invasiveness.

## Contribution

The paper identifies the KRAS Q22K mutation as a driver of TGF-β-induced partial EMT in early-stage colorectal cancer tumoroids.

## Key findings

- Early-stage tumoroids showed tumor-suppressive effects of TGF-β, while advanced ones were less responsive.
- KRAS Q22K mutation in tumoroids led to partial EMT, morphological changes, and increased invasiveness.
- TGF-β response was associated with elevated mesenchymal gene expression and matrix remodeling pathways.

## Abstract

Transforming growth factor beta (TGF‐β) exhibits complex and context‐dependent cellular responses. While it mostly induces tumor‐suppressive effects in early stages of tumorigenesis, tumor‐promoting properties are evident in advanced disease. This TGF‐β duality is still not fully understood, and whether TGF‐β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment, remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient‐derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell‐specific responses to TGF‐β. Using conditions allowing for the differentiation of PDTs, we observed TGF‐β‐induced tumor‐suppressive effects in early‐stage tumoroids, whereas more advanced tumoroids were less sensitive to the treatment. Notably, one tumoroid line harboring an atypical KRAS
Q22K mutation underwent partial epithelial‐to‐mesenchymal transition (EMT), which was associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell‐intrinsic responses to TGF‐β are critical in determining its tumor‐suppressive or tumor‐promoting effects.

TGF‐β has a complex role in cancer, exhibiting both tumor‐suppressive and tumor‐promoting properties. Using a series of differentiated tumoroids, derived from different stages and mutational background of colorectal cancer patients, we replicate this duality of TGF‐β in vitro. Notably, the atypical but highly aggressive KRAS

Q22K
mutation rendered early‐stage tumoroids susceptible to TGF‐β treatment and induced partial EMT and increased invasion.