Scientists may have pinpointed a gene they suggest could could be key to taming one of the world’s deadliest cancers – giving fresh hope to more effective treatments for a disease that has the lowest survival rate of all 20 common cancers.
Led by British scientists, but with collaboration from American counterparts, the study found that pancreatic cancer is able to shut down certain molecules in the HNF4A gene to help it spread and grow aggressively, reports The Independent.
This finding raises fresh hope in the hunt for more effective treatments for a disease that kills nearly 9 000 people in the UK every year.
Dr Maria Hatziapostolou, a scientist in Nottingham Trent University’s John van Geest Cancer Research Centre, said: “With pancreatic cancer, the survival of patients beyond five years has improved very little for some time and so it’s extremely important that we find new ways to better understand this disease, how it spreads and why it is so aggressive.
“This work, which has provided new understanding and knowledge of how the cancer behaves, will hopefully help pave the way for potential new treatments in the future.”
Pancreatic cancer is often diagnosed at an advanced stage when treatment options become limited, with more than half of patients dying within three months of diagnosis.
For the study, published in the journal Gastro Hep Advances, the researchers analysed healthy as well as pancreatic cancer tissue samples.
They found pancreatic cancers triggered a process known as DNA methylation, causing the beneficial HNF4A molecules to switch off and allowing tumours to grow rapidly.
Hatziapostolou said: “Loss of HNF4A drives pancreatic cancer development and aggressiveness and we now know correlates with poor patient survival.”
Dr Chris Macdonald, head of research at Pancreatic Cancer UK, which funded the study, said: “We desperately need kinder and more effective treatment options for pancreatic cancer. Most cases are diagnosed at a late stage, with 80% not being detected until after the disease has spread and is no longer operable.
“This is reflected in its poor survival rate – more than half of people with the disease die within three months of diagnosis.
“Improving our fundamental understanding of what makes pancreatic cancer grow and spread so rapidly is vital if we are to make much-needed breakthroughs.
“This project gives us new information on how pancreatic cancer is able to suppress certain molecules to help it spread aggressively around the body which, in turn, could lead to the development of more effective treatment options in the future.”
Scientists from the University of Nottingham, Stanford University and the University of California and Cedars-Sinai Medical Centre, Los Angeles, were also involved in the project.
Study details
Promoter Methylation Leads to Hepatocyte Nuclear Factor 4A Loss and Pancreatic Cancer Aggressiveness
Maria Hatziapostolou, Marina Koutsioumpa, Dimitrios Iliopoulos et al.
Published in Gastro Hep Advances on 23 April 2024
Background and Aims
Decoding pancreatic ductal adenocarcinoma heterogeneity and the consequent therapeutic selection remains a challenge. We aimed to characterise epigenetically regulated pathways involved in pancreatic ductal adenocarcinoma progression.
Methods
Global DNA methylation analysis in pancreatic cancer patient tissues and cell lines was performed to identify differentially methylated genes. Targeted bisulfite sequencing and in vitro methylation reporter assays were employed to investigate the direct link between site-specific methylation and transcriptional regulation. A series of in vitro loss-of-function and gain-of function studies and in vivo xenograft and the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) mouse models were used to assess pancreatic cancer cell properties. Gene and protein expression analyses were performed in three different cohorts of pancreatic cancer patients and correlated to clinicopathological parameters.
Results
We identify Hepatocyte Nuclear Factor 4A (HNF4A) as a novel target of hypermethylation in pancreatic cancer and demonstrate that site-specific proximal promoter methylation drives HNF4A transcriptional repression. Expression analyses in patients indicate the methylation-associated suppression of HNF4A expression in pancreatic cancer tissues. In vitro and in vivo studies reveal that HNF4A is a novel tumour suppressor in pancreatic cancer, regulating cancer growth and aggressiveness. As evidenced in both the KPC mouse model and human pancreatic cancer tissues, HNF4A expression declines significantly in the early stages of the disease. Most importantly, HNF4 loss correlates with poor overall patient survival.
Conclusion
HNF4A silencing, mediated by promoter DNA methylation, drives pancreatic cancer development and aggressiveness leading to poor patient survival.
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