Hogan, C. | bioRxiv Science

bioRxiv2020

Canonical Wnt signalling is activated during BEC-to-hepatocyte conversion in vivo and modulates liver epithelial cell plasticity in hepatic organoids

While it is recognized that the Wnt/{beta}-catenin pathway orchestrates hepatocyte proliferation in both homeostasis and injury, little is known about the importance of {beta}-catenin in biliary epithelial cell (BEC) plasticity. In this study, the dynamics of activation of the canonical Wnt pathway were investigated during BEC-to-hepatocyte conversion using as a model methionine/choline deficient (MCD)-injured livers where hepatocyte proliferation was compromised by the overexpression of p21. In this model, activation of {beta}-catenin was found an event associated with BEC reprogramming. Using ductal organoids to model BECs transitioning into hepatocytes, we found that activation of the Wnt/{beta}-catenin pathway in these cells promoted partial escape from a biliary fate and triggered the acquisition of progenitor cell features. Our data furthermore support that BECs are source of Wnt ligands and that Rspo proteins potentially act as the limiting factor controlling the activation of {beta}-catenin activation and BEC reprogramming during severe liver damage.

cell biology↗

bioRxiv2020

KRASG12D mutant cells are outcompeted by wild type neighbours in adult pancreas in an EPHA2-dependent manner.

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 neighbours 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 prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden 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 tumour suppressor in pancreatic cancer.

cell biology↗