Links between cell adhesion and cell cycle regulation in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma is one of the most lethal types of cancer, whose treatment has been barely improved in recent years. One of the reasons for the lethality of PDAC is the drug resistance and aggressiveness contributed by its dominant histological feature, a robust desmoplastic reaction. Accumulated evidence suggests that desmoplasia potentially drives the abnormal intracellular activity of epithelial cells, such as dysregulated cell cycle progression and migration, which leads to tumorigenesis and invasion. Integrins connect cells to extracellular matrix and bi-directionally transduce the signals between stroma and epithelial cells. Their overexpression can drive ECM remodelling and correlate with poor survival. Thus, an understanding of the associations between cell adhesion and cell proliferation regulation is needed. Previously, other work from the Humphries lab identified integrin a6b4 and hemidesmosome components as key components of the adhesion system in pancreatic ductal epithelial cells. Integrin a6b4 has been reported to modulate the Akt/PI3K, mTOR and MAPKRas signalling pathways and, therefore, regulate the cell cycle. This project aimed to investigate the links between integrin a6b4 with cell cycle regulation and elucidate the underlying mechanisms in pancreatic cancer. By using the immortalised human pancreatic ductal epithelial cell line H6c7 and pancreatic cancer cell lines as cell models, integrin a6b4 and HDs were identified as major adhesion systems in PDAC cells. Depletion of integrin b4 inhibited cell proliferation by arresting cells in G1 phase. A key underlying mechanism was the up-regulation of p27 expression at both protein and transcription level, enhanced nuclear accumulation of p27, and inhibited proteasome-mediated degradation. As a cell cycle regulator, accumulated p27 at the nucleus inhibits the activities of CDK-cyclin complexes and thus causes G1 arrest. Integrin b4-binding protein eIF6 and integrin ligand laminin 332 were found to be involved in p27 regulation, which builds the links between the extracellular matrix to the nucleus. In integrin b4-deficient cells, the increased role of integrin b1, the potential links between p27 and integrin a3, and the p27-regulatory role of CDK1, which mediates focal adhesion assembly, suggests a general remodelling of integrin-mediated adhesion, which regulates cell proliferation via modulating p27 activities. Overall, this project identified potential links between cell adhesion molecules and cell cycle progression in PDAC.

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Martin Humphries (Supervisor) & Claus Jorgensen (Supervisor)