Pancreatic cancer is one of the most aggressive tumor types with few effective treatment options. Now, a team of scientists has provided new insights into how targeting a common type of cells could have conflicting implications in treating the devastating disease.
Blocking expression of a protein called PKN2 changed the behavior of cells called fibroblasts, which help form an extracellular matrix around pancreatic tumors, researchers at Barts Cancer Institute (BCI) at Queen Mary University have found. Doing so could both promote and possibly help suppress tumor progression, the team described in a new study published in the journal Cell Reports.
Based on the findings, the researchers suggest drugs that target PKN2 could be developed—possibly as part of a combination therapy—for pancreatic cancer.
Fibroblasts are responsible for forming gel-like structures for tissues. They are best known in wound healing. Cancer lesions are like unhealed wounds, chronically activating fibroblasts to express growth factors to promote tumor progression. In pancreatic cancer, the process helps tumors resist treatment, making a group of activated fibroblasts known as cancer-associated fibroblasts an attractive target in pancreatic cancer research.
The BCI researchers previously showed that the PKN2 protein is a critical component in the activity of fibroblasts. This time around, they tested the effect of inhibiting PKN2 on fibroblast activation in pancreatic cancer.
In a 3D cell culture model, deletion of PKN2 suppressed the ability of pancreatic fibroblast cells to invade into the surrounding matrix when co-cultured with pancreatic cancer cells in spheroids, the researchers found. This suggests these altered cancer-associated fibroblasts became less mobile and less invasive.
Surprisingly, however, in the presence of PKN2-deleted pancreatic fibroblasts, tumors themselves grew more aggressively from the surface of the spheroids into the matrix. What’s more, without PKN2, cancer-associated fibroblasts switched to an inflammatory state, which can promote more aggressive and invasive tumor growth. But such a state could theoretically also make tumors more responsive to immunotherapy.
Similar results were found in mouse models of pancreatic cancer. Compared with mice with normal PKN2, rodents with their PKN2 deleted had larger tumors and increased local secondary tumor formation. This finding suggests that crippling activated fibroblasts appears to limit the tumor-restraining function of pancreatic fibroblasts to drive a more locally advanced disease, the researchers noted in the study.
“When activated through PKN2, fibroblasts can actually act as a defense mechanism to limit cancer spread by keeping the cancer cells tightly compacted within the tumor,” Shinelle Menezes, a co-first author of the study, said in a statement. “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 tumor.”
The reciprocal interaction between cancer-associated fibroblasts and tumors has drawn much interest in making these common cells a potential target for cancer therapy. However, as the researchers noted, targeting pancreatic fibroblasts has yielded often conflicting results.
In one attempt, a research team led by scientists at the Salk Institute previously found that reprogramming pancreatic fibroblasts with the vitamin D receptor agonist calcipotriol—an old psoriasis treatment—could revert activated cells into a quiescent state. The approach helped the chemotherapy gemcitabine better penetrate pancreatic tumors and extended survival of mice.
The complex nature of cancer-associated fibroblasts means a combination therapy approach is likely necessary for targeting PKN2, the BCI team argued. The team hopes to identify drugs to target PKN2 to better understand the pathway’s role in pancreatic and other cancers, Angus Cameron, the study’s senior author, said in a statement.
Cameron and colleagues are now studying the profile of immune cells within pancreatic cancer tumors. In the future, a PKN2-targeting drug, by breaking down protective fibroblasts, might sensitize pancreatic tumors to immunotherapy, they suggested.