Harnessing the potential of embryo-derived pancreas organoids to model early tumorigenesis (360G-Wellcome-210198_Z_18_Z)

Epithelial tissues maintain homeostasis through competitive cell-cell monitoring systems that detect and eliminate defective or mutant cells1-3. Retention of damaged or mutant cells would impair tissue function and initiate tumourigenesis. We have identified an evolutionarily conserved mechanism of cell competition that drives the segregation and elimination of Ras-transformed cells from simple epithelia4-6. KRas mutations (KRasG12D) are the principal oncogenic drivers of human pancreatic ductal adenocarcinoma (PDAC)7, making it an ideal model to test the significance of KRas driven cell competition. Our current data show that KRasG12D cells are lost from healthy pancreas tissues, suggesting that the normal niche may prevent early tumourigenesis. Current experimental pancreas models limit our ability to probe the biology of cell competition at the cellular level. The goal of this proposal is to grow fully differentiated pancreas organoids in culture, mosaic for KRasG12D expression. Organoids recapitulate the cellular complexity, plasticity and spatial organisation of tissues8,9. We will combine this accessible cell-based platform with advanced imaging techniques, to determine how the normal cell niche prevents expansion of KRasG12D cells, and how additional p53 mutations drive disease. Future work will investigate Eph-ephrin signalling and changes in cell polarity in early tumorigenesis.