Oncogenic KRAS cells use Wnt signalling and cell dormancy to override homeostatic cell elimination mechanisms in adult pancreas

Epithelial tissues use homeostatic defence mechanisms to actively remove aberrant or poorly functioning cells to maintain tissue health. We show that when present in tissues in low numbers, cells expressing cancer-causing mutations compete with normal cells for survival and are often eliminated. This implies that tumour initiation would require mechanisms whereby mutant cells override tissue homeostasis and remain in a tissue; however, the biology of these initial events is poorly understood. Here, we use an in vivo model of sporadic tumorigenesis in the adult pancreas to show that cell elimination processes are inefficient and a proportion of KrasG12D or p53R172H expressing cells are never eliminated from the epithelium. Using RNA sequencing of non-eliminated mutant populations, we reveal a general activation of the non-canonical Wnt pathway. We demonstrate that non-eliminated KrasG12D cells express cell dormancy and diapause gene signatures, suggesting non-eliminated KRasG12D cells adopt a dormant cell state in vivo . To model cell competition in vitro , we used established MDCK cell systems to show that active Wnt or cell cycle arrest blocks elimination of RAS mutant cells from normal epithelial cell sheets. Importantly, we demonstrate that Wnt signalling is a general mechanism that blocks elimination of some KrasG12D and p53R172H cells from pancreas tissues in vivo . Our results suggest that mutant cells activate Wnt and/or a dormant cell state to avoid homeostatic tissue defence mechanisms and survive in the adult pancreas. ### Competing Interest Statement The authors have declared no competing interest.