The promise of a potential pancreatic cancer target has been thrown into doubt as a new study finds blocking its function could lead to a more aggressive form of the disease.
The molecule in question is PDX1 – a transcription factor critical for development of the pancreas. In pancreatic cancer, PDX1 has been shown to contribute to the growth of tumours.
As a result, many believe that blocking the function of PDX1 in pancreatic cancer could be an effective means of stopping the cancer from growing.
A new study from researchers at Michigan Medicine and the University of California San Francisco has put this belief in doubt.
Initially, the team investigated the function of PDX1 in three different mouse models: one normal mouse, one with pre-cancerous pancreatic cells and one with pancreatic cancer. The team found that PDX1 maintained the identity of normal pancreatic cells and was required to maintain normal cell function.
However, when they investigated PDX1 function in subtypes of pancreatic cancer, the team found that those pancreatic cancers with lower PDX1 levels were actually more aggressive with tumours exhibiting little-to-no PDX1 expression leading to the worst outcomes.
The results suggest that PDX1’s role in pancreatic cancer is not as simple as many believe with its function changing as a tumour develops, rather than maintaining the same function throughout the growth of a tumour.
“PDX1 has been reported as a target to treat cancer. The reality is that might not be the best idea,” said study author Howard Crawford, professor of molecular and integrative physiology and of internal medicine at the University of Michigan Medical School. “We showed the loss of PDX1 is actually promoting the aggressiveness. Losing PDX1 means the cells lose their identity.”
The reason for PDX1’s loss resulting in more aggressive tumours is believed to be due to its restriction of cell mobility. Once PDX1 is lost, normal cells can transition into highly mobile cells likely to metastasise.
In tumours with PDX1, the molecule could still be carrying out its normal function of preventing cancer cells from moving away from their primary site.
A similar juxtaposition of molecular function can be seen in breast cancer where oestrogen receptor can be over-expressed by cancer cells, making it a perfect target for treatment. Unfortunately, these cancers can become resistant to such therapies, resulting in more aggressive and difficult-to-treat types of cancer.
“Inhibiting PDX1 can be temporarily effective. But we need to be prepared for the mechanism of resistance and for the likelihood of making the cancer more aggressive,” said Crawford.