Work

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

Year: 2025

Type: article

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.

Source: Molecular Oncology

DOI: 10.1002/1878-0261.70014