Gene Editing Corrects Cancer-Linked Mutations in Patient-Derived Colon Organoids

Gene Editing Corrects Cancer-Linked Mutations in Patient-Derived Colon Organoids
By Aline Habib, Rose Mamistvalov, Mira Malcov, and Prof. Dalit Ben-Yosef
Published in Cancer Gene Therapy, July 2025

Using human embryonic stem cells (hESCs) derived from embryos carrying three distinct APC germline mutations, the researchers created patient-specific colon organoids to study early cancer development. Two mutations (FAP1 and FAP2) severely impaired the organoids’ ability to differentiate, while a third (FAP3) produced complex, healthy-like structures.

By applying CRISPR/Cas9 genome editing to correct the APC mutations in FAP1 and FAP2 lines, the team fully restored normal organoid development, confirming that these single genetic alterations directly drive the early pre-cancerous phenotype. Advanced structural modeling using AlphaFold2 revealed that truncated APC proteins in FAP1 and FAP2 form abnormal, highly stable heterodimers with the full-length APC, disrupting its tumor-suppressive role through a dominant-negative mechanism.

This work not only strengthens the genotype-phenotype link in FAP but also points to new personalized strategies for early intervention before tumors develop.

Full article: https://doi.org/10.1038/s41417-025-00923-7