DO NOT RE-DEPOSIT UNTIL WE HAVE HEARD FROM AUTHOR OR CORNELIA WILSON The pivotal role of sortilin deregulation and extracellular vesicles in Non-Small Cell Lung Cancer

Abstract

The neurotensin receptor-3 also known as sortilin is a member of a small family known as vacuolar protein sorting 10 protein domain (Vps10p). It is firstly discovered in the human brain;however its expression is not only confined to the nervous system but is expressed in many tissues. Sortilin plays various roles in the cell as a receptor or a co- receptor, transporting protein to the plasma membrane or to the endocytic pathway and to the lysosomes for protein degradation. In addition, the extracellular domain of sortilin can be released into the culture media, and also through extracellular vesicles as a complex with other tyrosine receptor kinases such EGFR and TrkB which can affect the tumour microenvironment and activate signalling pathways in the recipient cells. Sortilin levels are deregulated in a number of conditions, including neurological disorders and cancers like lung cancer.

To investigate how deregulated sortilin expression affects the initiation and progression of NSCLC. Sortilin stable NSCLC cell lines with different sortilin expression levels were generated, in which the SK-MES-1 cell line has sortilin overexpression clones while the H358 cell line has sortilin knockdown clones. The cell viability, migration, and apoptosis were assessed, followed by studying the effect of the cancer cell-derived EVs on the cells’ microenvironment and the protein and gene expression levels. Overexpression and knockdown of the SORT1 gene affected the cells' proliferation andmigration, as well as the EVs' size, concentration, and proteomic contents. Also, the autologous EVs treatment showed a change in cell proliferation, and the allogenic treatment showed a change in cell migration and specific protein and gene levels that control several signalling pathways. Therefore, the major findings from this project imply that sortilin may play a part in the initiation and spread of NSCLC. Thus, modulating sortilin expression in lung cancer could be a promising therapeutic approach.

Date of Award	2023
Original language	English