Signalling protein may be Achilles heel of pancreatic cancer

Scientists at the US Salk Institute for Biological Studies, along with an international team of collaborators, have uncovered the role of a signalling protein that may be the Achilles heel of pancreatic cancer. Their study has been published in the journal Nature.

The National Institutes of Health (NIH) projects that pancreatic cancer will be the second-leading cause of cancer-related deaths in the United States by 2030. This is because advanced pancreatic cancer is often symptomless, leading to late diagnosis only after metastatic disease has spread throughout the body. Additionally, tumour cells are encased in a ‘protective shield’ — a microenvironment conferring resistance to many cancer treatments.

Now, Salk Institute scientists have shown that pancreatic stellate cells — resident cells typically dormant in normal tissue — become activated and secrete proteins to form a shell around the tumour in an attempt to wall off and contain it. The activated stellate cells also secrete a signalling protein called leukaemia inhibitory factor (LIF), which conveys stimulatory signals to tumour cells to drive pancreatic cancer development and progression. Results suggest LIF may be a useful biomarker to help diagnose pancreatic cancer more quickly and efficiently.

“Most solid cancers are not caused by abnormality in a single cell type,” said Yu Shi, a postdoctoral fellow at Salk and first author of the paper. “Instead, the tumour cells live and work cooperatively with surrounding normal cells in the tissue. They can also ‘go bad’ together as an unholy alliance, which can lead to cancer.

“If we can understand how the different types of cells interact with each other within the tumour microenvironment, then we may uncover a good target to eventually cure the disease.”

To understand the method of communication between the pancreatic stellate cells and the cancer cells, the researchers first developed cell cultures to analyse the proteins that were being exported from the stellate cells. They suspected that stellate cells were communicating with tumour cells using specific signalling proteins, but until now, they did not know which ones.

“We wanted to see what kind of signalling was activated in the tumour cells in pancreatic cancer,” said Shi. “LIF is an important factor that normally helps stem cells maintain their developmental potential during the embryonic period, but usually vanishes in adulthood. We found that activated stellate cells are secreting LIF, which acts on neighbouring cancer cells.”

After pinpointing LIF as the critical communicator, the researchers wanted to better understand the function of LIF during pancreatic cancer progression to evaluate the protein as a potential therapeutic target. By observing the effects on tumour growth of blocking or destroying LIF (both render the protein non-functional) in a mouse model of pancreatic cancer, the researchers could examine how LIF affects tumour progression and response to treatment. Both techniques independently showed that without functional LIF signalling, tumour progression slowed down and responses to chemotherapeutic drugs used in treating human cancer (such as gemcitabine) were improved.

“Previous studies have shown that if you kill the pancreatic stellate cells, then the tumours get worse,” said Salk American Cancer Society Professor Tony Hunter. “This means that you don’t want to destroy the pancreatic stellate cells that secrete signalling factors, but rather want to stop them from delivering the stimulatory signals to the tumour cells.”

In addition to checking the consequences of LIF blockade in mice, the researchers also examined the levels of LIF in tumour tissue and blood from human pancreatic cancer patients. They found high levels of LIF in both the patients’ tumours and blood. They also found a significant correlation between LIF levels, tumour progression and patient response to chemotherapy. These early findings suggest that LIF holds promise as a biomarker for pancreatic cancer stage and treatment response.

“We were excited to find that elevated LIF levels were significantly correlated with tumour cell status and the response to chemotherapy,” Shi said. “These results are consistent in both the mouse model and human pancreatic cancer.”

Currently, the only FDA-approved biomarker for pancreatic cancer is a carbohydrate called CA19-9. This study found that LIF was an accurate and independent measure of pancreatic cancer, and was a better indicator of therapeutic response than CA19-9.

“One possibility would be to use a combination of the two biomarkers to get a better picture of the disease status and response,” said Prof Hunter. “We also think that the anti-LIF antibody therapy could be useful, in combination with other therapeutics, to treat pancreatic cancer. This is very translatable research, and it’s nice to be working on a project that has the ability to make a direct impact on a deadly human cancer.”

A phase 1 clinical trial has now been initiated by Northern Biologics, a Canadian company, to test the effect of treatment with a monoclonal (synthetic) antibody that binds to and blocks LIF from signalling in advanced pancreatic and other types of cancer. The results of this trial are awaited with great interest, according to Prof Hunter.

“Over my 40-year career, this is undoubtedly the closest I’ve come to potentially developing a new cancer drug,” he said. “So I’m particularly excited by that.”

Image caption: LIF (green), expressed mainly in activated pancreatic stellate cells, is shown along with immune cells (purple) and cancer cells (yellow) in pancreatic cancer tissue. Image credit: Salk Institute.

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