Research identifies new way to halt pancreatic cancer invasion by targeting healthy cells

Pancreatic cancer tumours are made up of cancer cells and non-cancerous cells that have been hijacked by the cancer. To grow and spread, pancreatic cancer cells need to communicate with the other cells in their environment through signalling pathways. Blocking these signalling pathways to silence the communication between cancer cells and surrounding cells could offer new approaches for cancer therapy.

In this study, the researchers were interested in the role of the Fibroblast Growth Factor (FGF) signalling pathway. This pathway is important for normal tissue development in the embryo as well as wound repair, but when it is activated inappropriately it can lead to the development of many cancer types including breast and pancreatic cancer.

To interrogate FGF signalling in pancreatic cancer, the researchers created 3D models known as spheroids made up of pancreatic cancer cells and non-cancerous ‘stellate’ cells grown together in a gel that mimics the tumour’s microenvironment in the pancreas. Stellate cells help to create a dense, fibrotic layer around pancreatic tumours, known as the ‘stroma,’ which acts as a physical and chemical barrier around the tumour and limits the efficacy of cancer treatments.

By fluorescently staining the cells in the spheroids and watching them under the microscope, the team observed that the stellate cells guide the cancer cells away from the main cluster of cells, leading the invasion into the surrounding gel matrix.

When the team introduced a drug into the spheroids to block a key chemical messenger of the FGF pathway, known as FGFR1, invasion was halted. Surprisingly, the researchers found that FGFR1 was activated in the stellate cells rather than the cancerous cells, suggesting that the stellate cells are a key driver of cancer spread.

Under normal circumstances, FGFR1 sits on the surface of cells. However, in their models, the team found that FGFR1 was located in the nucleus of the stellate cells that were leading invasion.

Further investigations (using a specialised method called ChIP-Seq) revealed that once inside the nucleus, FGFR1 attaches to the cell’s DNA to upregulate the expression of a gene called NRG1. Cancer cell invasion could be reduced either by preventing FGFR1 from entering the nucleus of the stellate cells or by blocking the expression of NGR1.

Professor Richard Grose, co-lead author of the study, said:

“Our findings highlight, for the first time, that nuclear FGFR1 in stellate cells drives pancreatic cancer invasion by upregulating NGR1, and that there may be multiple ways to target the FGF signalling pathway to slow down cancer spread.”