Molecular switch found to drive pancreatic cancer progression

New research from our Carroll Group has identified a molecular mechanism that helps explain how pancreatic ductal adenocarcinoma progresses, offering a potential path toward more targeted treatments. 

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. PDAC itself can be divided into two main types based on how genes are switched on or off. This process is controlled by proteins called transcription factors, which can change how the cancer develops and changes over time. 

The team focused on one of these transcription factors, called FOXA1, which has been linked to the spread of pancreatic cancer. By studying the proteins that interact with FOXA1, the researchers found that it forms connections with another group of transcription factors known as HNF4. In particular, they discovered that one family member, HNF4G, plays a key role early in the disease. 

As the cancer progresses, HNF4G activity falls and FOXA1 takes over, activating a different set of genes that promote metastasis, the process by which cancer spreads to other parts of the body. This shift represents a newly identified context specific role for these proteins “transcription factor switch”. 

As a result, the discovery of HNF4G’s role in early-stage pancreatic cancer opens up a potential new way to develop targeted treatments, particularly for patients with the classical subtype of PDAC. Understanding how HNF4G and FOXA1 work together as the disease progresses could also help clinicians better classify tumours and tailor treatments to each stage of the disease. 

This work was made possible with the support of the genomics, proteomics, pharmacokinetics and bioanalytics, histopathology, pre-clinical genome editing,  bioinformatics and research instrumentation core facilities at the Cancer Research UK Cambridge Institute.

Prof Jason Carroll, Deputy Director and senior author, said “By leveraging our tools and insight from other cancers, we could apply our methodological approaches to identify the key proteins that drive one major subtype of pancreatic cancer. What it revealed was an unexpected, but complex process where one protein called HNF4G is critical for tumour growth, but a second protein called FOXA1 takes over to drive the cancer’s spread and metastasis. This work revealed that similar proteins can be used in completely different cancers, but it also showed that the way these proteins function can be very different from one cancer type to another. The work sheds light on the key events that ultimately culminate in pancreatic cancer growth and spread”