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

• DOI: 10.1016/j.cub.2021.03.094
• Publication Date: 2021-04-22T16:04:27Z
• Authors: William Hill; Andreas Zaragkoulias; Beatriz Salvador-...; Geraint J. Parfitt; Markella Alatsati...; Ana Padilha; Sean Porazinski; Thomas E. Woolley; Jennifer P. Morton; Owen J. Sansom; Catherine Hogan
• Keywords: Male; 0301 basic medicine; 0303 health sciences; Receptor, EphA2; Tumor Suppressor Proteins; Oncogene Protein p21(ras); Cadherins; Article; 3. Good health; Pancreatic Neoplasms; Mice; 03 medical and health sciences; Genes, ras; Cell Competition; Cell Adhesion; Animals; Female; Pancreas; Cells, Cultured

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