Pancreatic cancer and depression - Investigating the role of neuropeptides in the development of precursor lesions in pancreatic ductal adenocarcinoma

PDAC account for 90% of pancreatic cancers and are estimated to be the second greatest cause of cancer-relate mortality by 2030. The survival rate for PDAC is exceptionally low (5-year survival = 3%) owing to the typically late stage of diagnosis. PDAC is often instigated through occurrence of precursor lesions which are undetected and progress over several years, typically undergoing a series of major molecular events (i.e KRAS, CKDN2A, TP53, BRCA 2 & SMAD4 mutations).

This project aims to identify and investigate the function of neuropeptides during the maturation of precursor lesions into PDAC. In addition to their potential role in the high levels of psychiatric disorders (i.e. depression) observed preceding, during and following diagnosis of PDAC. Research objectives:

This project begins to ask two major questions that are opposite sides of the same coin:

A. Are psychiatric disorders early warning signs of precursor lesions and/or PDAC development, caused by cancer induced perturbation of neuropeptide signalling? Thus, leading to behavioural changes, symptoms and/or reductions in psychiatric resilience that leave individuals vulnerable to the development of psychiatric disorders.

B. Are psychiatric insults, such as acute or chronic traumas and stress, causative of dysfunction and/or a reduction in immunosurveillance that enables the development of previously controlled pancreatic lesions into PDAC, via the perturbation of neuropeptides? The specific investigative questions are:

1) Does alterations in neuropeptide signalling impact PDAC precursor lesions development, caused by stress and psychiatric disorders? 2) What are the specific binding targets of neuropeptides of interest, at the molecular and cellular levels? 3) Does altered neuropeptide signalling impact the tumour microenvironment to influence PDAC development?

Translational potential:

This project offers a unique investigation into the molecular biology that links the elevated levels of psychiatric diseases in pancreatic cancer. By doing so, this lays the foundation for understanding the brain-cancer axis and how we may augment it for improved patient outcomes. Moreover, it also underpins the potential development of novel early screening methods in PDAC patients.

Additionally, further establishment of the biological basis of psychiatric illnesses in cancer patients, and its influence on cancer development and treatment, will greater substantiate the need and importance of more robust psychiatric support in patients and revision of current policy.