Investigating the Role of Polarity Regulators in Pancreatic Ductal Adenocarcinoma (PDAC) Pathogenesis and Therapy.

Description

Background

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies, with a five-year survival rate of ~10%. The lack of effective therapeutic options and the high incidence of chemoresistance underscore the urgent need to elucidate the molecular mechanisms driving PDAC development and progression.

Loss of cell polarity, a hallmark of epithelial neoplasia development, is critical during the progression from pancreatic preinvasive lesions to invasive PDAC. Altered expression of cell polarity regulators leads to dysregulation of oncogenic and tumour suppressive pathways, thereby promoting tumour progression. Further evidence indicates that inactivation of polarity genes drives resistance to chemotherapy and correlates with poor outcomes.

Emerging evidence, including work from our group and others, has demonstrated that mutations in polarity regulators are relevant genetic events in PDAC development. These findings highlight the need to investigate the tumour suppressive functions of polarity genes in PDAC and their clinical potential to identify novel strategies for patient stratification and therapeutic intervention.

Hypothesis: A better understanding of polarity signalling during PDAC development will reveal predictive biomarkers of drug response and molecular targets for therapeutic intervention in PDAC.

Aim and experimental strategy

This interdisciplinary project integrates genetic, pharmacological and clinical approaches to investigate the biological and therapeutic relevance of polarity regulators in PDAC.

1.- Molecular (viral-mediated shRNA/CRISPR) and cellular biology (2D/3D cell cultures) approaches will be employed to assess the tumour suppressive activities of polarity regulators in PDAC cells.

2.- Pharmacological and transcriptomic approaches will be used to identify molecular pathways associated with drug response. 

3.- Clinical relevance of the findings will be evaluated in a collection of human PDAC samples.

Impact

This project introduces an innovative and comprehensive strategy designed to address critical unmet needs in PDAC research, with a strong focus on achieving meaningful translational impact. By targeting polarity regulators, we aim to uncover novel therapeutic targets and predictive biomarkers, ultimately striving to significantly improve clinical outcomes for PDAC patients.

Training

This PhD project will provide training in cancer biology and will offer a framework to develop their skills in molecular and cellular biology. Work will be undertaken in collaboration with members of the Pancreatic Group in Liverpool, including basic and clinical researchers. The student’s project will synergise with other research aiming at addressing critical gaps in PDAC pathogenesis and therapy.

Application process

The project is suited to a student with at least a good B.Sc. Upper Second in Cancer Biology, Biological Sciences, or related subjects, and evidence of lab experience. Applications should be made via CV and cover letter, sent to Dr Perez-Mancera (pedro.perez-mancera@liverpool.ac.uk) Applications will be reviewed until a suitable candidate is appointed. This is a self-funded project.