EGF and EREG regulate early oncoprotein-mediated tissue transformation in intestinal organoids.

Early oncoprotein-mediated tissue transformation in intestinal organoids is regulated by the EGF and EREG signaling pathways, according to a recent study. Somatic mutations, combined with abnormal extracellular signaling cues, contribute to tumor development. The abundance and affinity of EGF-family ligands for EGFR impact tissue development, particularly in mouse small intestinal organoids (mSIOs).

These organoids exhibit a balance between crypt proliferation and villus differentiation that can be altered by the medium ligand composition.

To investigate this further, the researchers generated a Ptprg KO organoid line using CRISPR/Cas9 technology and two organoid lines with synthetic bio-orthogonal expression systems for KRASG12V and {beta}-Ctn4A. These systems were activated by membrane-diffusible ligands TMP or TMP-Cl. The team observed that acute oncogenic activity did not change organoid growth in media containing 50 ng/mL EGF, but organoids grown without EGF showed differential growth in the crypt region.

Interestingly, EREG and sub-saturating EGF (0.5-5 ng/mL) treatments affected crypt/villus development differently in each organoid line. The researchers also measured organoid morphology and found that crypt domain spatial distribution, while independent of crypt area, required either EGF or EREG. This finding underscores the crucial role of both proliferation and crypt organization in oncogenic tissue transformation.