Changing Fibroblast Behaviour May be Key to Pancreatic Cancer Treatment

Dr Rob Hicks

January 26, 2022

In a new finding, researchers from Barts Cancer Institute at Queen Mary University, London, have discovered more about how fibroblasts actually help pancreatic cancer develop, raising the possibility of new treatments for this tough to treat cancer.

Dr Shinelle Menezes, postdoctoral researcher and joint first author of the study said: "Fibroblasts are like the gatekeepers of pancreatic cancer tumours", protecting pancreatic cancer from treatment by producing a dense stroma (scar tissue) around the tumour.

This stroma, say the researchers, "blocks chemotherapy from reaching the tumour and suppresses the immune system, making immunotherapy ineffective". Fibroblasts also play a role in helping the cancer to spread around the body.

Both Positive and Negative Roles

In their study, published in Cell Reports , the researchers identified that blocking the expression of the protein PKN2 in the fibroblasts around the tumour caused the tumour to grow more aggressively. The fibroblasts had switched to a less mobile and invasive state and had instead promoted inflammation – something that is known to make tumours more aggressive but that can also make them more responsive to immunotherapy.

Dr Menezes pointed out that: "Our findings suggest that they [fibroblasts] 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," Dr Menezes continued.

She went on to explain how blocking PKN2 suppresses the ability of fibroblasts to contain the cancer cells. However, she said that this "also means that they may let more immune cells into the tumour".

Potential New Drug Target

Dr Helen Rippon, chief executive at the charity Worldwide Cancer Research, said: "Pancreatic cancer remains stubbornly stuck as one of the least survivable cancers, with fewer than 1 in 10 people living 5 years after diagnosis." 

She added: "It is difficult to treat because current cancer drugs do not work well."

The researchers say that their new findings "expose PKN2 as a potential new drug target to alter the development and treatment sensitivity of pancreatic cancer".

Dr Angus Cameron, lead author of the study, said: "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 Menezes said that their novel finding could have broad implications for how targeting stromal fibroblasts can help to treat cancer.

A Major Step Forward

Dr Cameron said: "Our study contributes to the understanding of the biology of the invasive process in pancreatic cancer, and the roles that fibroblasts play." He added that in their future work they hope to identify effective drugs to target PKN2.

Maggie Blanks, CEO at the 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."

Dr Cameron and his team are now studying the altered profile of immune cells within pancreatic cancer tumours, and hope that in the future the right combination of immunotherapy and a PKN2-targeting drug could be an effective way of treating pancreatic cancer.

The research was supported by the charities Worldwide Cancer Research, Pancreatic Cancer Research Fund, Pancreatic Cancer UK, Cancer Research UK, and the Academy for Medical Sciences.

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