Researchers have found fresh hope for new treatments for pancreatic cancer by uncovering that the disease’s progression is linked to the shutdown of molecules in crucial genes.
A recent study indicates that a specific gene, which ordinarily helps to slow down the growth and spread of pancreatic cancer, is 'switched off' in the disease's early stages.
This deactivation allows the tumour to grow rapidly and become more aggressive.
Scientists at Nottingham Trent University, the University of Nottingham, Stanford University, the University of California, and Cedars-Sinai Medical Centre, Los Angeles, found that the molecule HNF4A suppressed pancreatic cancers, regulating their growth and aggressiveness.
They observed that HNF4A was significantly shut down in the early stages of the cancer, declining further as the disease spread.
On average, there are more than 10,400 new cases of pancreatic cancer in the UK each year, and more than 9,500 people will die from the disease.
Fewer than seven per cent of patients will survive pancreatic cancer beyond five years, and there are challenges around screening, diagnosis and treatment.
Pancreatic cancer is typically diagnosed at an advanced stage when the optimal treatments are no longer suitable for the majority of patients, and there can be significant resistance to radiotherapy and chemotherapy.
As part of the study, the researchers analysed pancreatic cancer and healthy tissues to reveal the exact mechanism tumours use to switch off the expression and beneficial function of HNF4A.
Previous research has examined the beneficial role of HNF4A in human physiology, especially in gastrointestinal tract tissues, including the pancreas, liver, and intestine.
Disturbance or loss of HNF4A activity is known to lead to various types of disease, including cancer, diabetes and inflammatory bowel diseases.
The researchers uncovered the molecule's tumour-suppressive role by integrating the patient data with different pharmacological and genetic approaches.
When correlating the molecule’s expression alongside the patient data, they found that low expression of HNF4A was linked to poor patient survival.
While several studies have examined how cells behave in pancreatic cancer, the underlying mechanisms remain largely unknown.
The researchers argue this new understanding will help with the potential development of new standalone or combined treatments for pancreatic cancer.
Lead researcher Dr Maria Hatziapostolou, a Nottingham Trent University’s John van Geest Cancer Research Centre scientist, said: ‘Not only have we uncovered the tumour-suppressive role of HNF4A, but also how it is switched off from the very early stage of the disease. We found that DNA methylation modifications are added to the specific gene to shut it down. Loss of HNF4A drives pancreatic cancer development and aggressiveness, and we now know it correlates with poor patient survival. We hope this new understanding of the mechanism through which this occurs will help pave the way for new therapeutics to help fight the disease.’
The study is published in the journal Gastro Hep Advances.
It was funded by Pancreatic Cancer UK, the National Institutes of Health in the US, a donation by the Jackson Family in memory of Corina Bennett and a charitable grant from the Mayor of Gedling in Nottinghamshire.
