Pancreatic cancer tumours are surrounded by thick scar-like tissue known as the stroma, which limits drugs from reaching the tumour inside and fibroblasts make up the majority of this tissue. The stroma also limits the body’s own immune cells from reaching the tumour, which is one of the key reasons why new treatments such as immunotherapies (which encourage the body’s immune cells to fight cancer) have little benefit in treating pancreatic cancer when they have shown good results with other cancers.
Fibroblasts are very mobile, invasive cells that help cancer cells to escape the tumour and spread around the body. Because of this, the research team at Barts Cancer Institute, Queen Mary University of London, led by Dr Angus Cameron, wanted to find out whether blocking the production of a protein (called PKN2) that enables fibroblasts to become mobile would affect the way that pancreatic cancer develops, and whether it would prevent the cancer from spreading.
The study, published in the journal Cell Reports, was conducted on pancreatic cancer cells and mice. The team found two new things:
Firstly, when they blocked the production of PKN2 within the fibroblasts, the fibroblasts stopped being mobile and invasive – but, surprisingly, this caused the cancer cells to become more invasive and meant that the tumours in the mice grew more aggressively.
However, further investigations revealed that while blocking PKN2 curbed the movement of the fibroblasts, it switched them to a different type of fibroblast – one that promotes inflammation and activates the body’s immune system, allowing immune cells into the tumour.
This suggests that although targeting PKN2 in fibroblasts makes pancreatic tumours more aggressive, it may also have the potential to make them more responsive to immunotherapies.
Dr Shinelle Menezes, a postdoctoral researcher in Dr Cameron’s laboratory and joint author of the study said: “Fibroblasts are like the gatekeepers of pancreatic cancer tumours, and our findings suggest that they can have both positive and negative roles to play in cancer progression.”
“We found that, when activated through PKN2, fibroblasts can actually act as a defence mechanism to limit cancer spread by keeping the cancer cells tightly compacted within the tumour. Blocking PKN2 suppresses the ability of fibroblasts to contain the cancer cells; however, it also means that they may let more immune cells into the tumour. This novel finding could have broad implications for how we target stromal fibroblasts to treat cancer.”
Dr Cameron added: “To improve the outcomes for patients, we need to identify new strategies to target cancer cells as well as the normal cells supporting cancer growth, and find ways to help the body’s immune system fight back against cancer.”
Dr Cameron and his team now hope to identify effective drugs to target PKN2 which in the future could be used in combination with immunotherapy as a new treatment option for pancreatic cancer.
Maggie Blanks, CEO at Pancreatic Cancer Research Fund, said: “Anything we can do to find a way to improve the effect of immunotherapy on pancreatic cancer would be a major step forward, so it’s encouraging that this research is contributing to the knowledge in this area. We’re looking forward to hearing more about how this research progresses.”