EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas

摘要: Summary As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition adult relevance of this process to remain incompletely understood. Here, investigate how pancreas maintains tissue health in vivo following sporadic expression oncogenic Kras (KrasG12D), key driver mutation human pancreatic cancer. We find that when present low numbers, KrasG12D mutant cells outcompeted cleared from exocrine endocrine compartments in vivo. Using quantitative 3D imaging, show before being cleared, lose cell volume, pack into round clusters, E-cadherin-based cell-cell adhesions decrease at boundaries neighbors. identify EphA2 receptor as an essential signal clearance In absence functional EphA2, do not alter volume or shape, increase retained The retention KRasG12D leads early appearance premalignant intraepithelial neoplasia (PanINs) Our data remodel clear maintain health. This study provides evidence support conserved role Ras-driven epithelial suggests novel tumor suppressor