New Druggable Target for Pancreatic Cancer Discovered

Pancreatic cancer occurs within the tissues of the pancreas, which is a vital endocrine organ located behind the stomach. The pancreas plays an essential role in digestion by producing enzymes that the body needs to digest fats, carbohydrates, and proteins. pancreatic cancer makes up about 3 percent of cancer diagnoses in the United States and 7 percent of cancer deaths

A new mouse study by researchers led by Angus Cameron, PhD, senior lecturer at Barts Cancer Institute at Queen Mary University of London, reveals new insight into how healthy cells help pancreatic tumors develop, which may pave the way for the development of new drugs for pancreatic cancer. The researchers discovered that blocking the expression of a protein, called PKN2, changed the behavior of healthy cells around the tumor called fibroblasts. Their findings suggest targeting fibroblasts may change their behavior and affect how pancreatic cancer develops. When the researchers blocked expression of PKN2 in the healthy cells of a preclinical model of pancreatic cancer, the tumor grew more aggressively. Their findings are published in Cell Reports.

The authors found that PKN2 regulates both the activation of mouse PSCs and mouse embryonic fibroblasts (MEFs) into myofibroblasts. They also identified PKN2 as a novel regulator of the mechano-sensor YAP, which is central to myofibroblast function. Intriguingly, loss of PKN2 in PSCs resulted in a switch in cellular invasive mechanism in heterotypic spheroid cultures, suppressing PSC invasion while promoting polarized epithelial outgrowth. Further, stromal deletion of PKN2 in vivo results in more locally invasive tumors, with accompanying pro-invasive changes to the matrisome signature. According to the authors, preventing myofibroblast differentiation in malignancy may therefore limit the tumor-suppressive role of fibroblasts, counter to the dogma that CAFs support cancer invasion. Their work also highlights the potential impact that targeting specific fibroblast phenotypes may have on functionally distinct CAF subtypes in PDAC.

“Fibroblasts are like the gatekeepers of pancreatic cancer tumors, and fibroblasts may have both positive and negative roles to play in cancer progression.

The authors found that, 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. 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. This novel finding could have broad implications for how we target stromal fibroblasts to treat cancer.

Together, the authors identified PKN2 as a potential target to modulate the pathological activation of fibroblasts. However, preventing fibroblast activation could also suppress the ability of myofibroblasts to contain and suppress malignant tumor growth by altering the fibroblast matrisome and secretome. The fibrotic, hypovascular nature of the pancreatic cancer stroma nonetheless remains a critical barrier to both chemo- and immunotherapy. Targeting fibrosis to improve therapy responses while retaining the tumor-suppressive functions of fibroblasts thus presents a clinical dilemma.

The researchers are now studying the altered profile of immune cells within pancreatic cancer tumors. To improve the outcomes for patients, the research team aim 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. Their study contributes to the understanding of the biology of the invasive process in pancreatic cancer, and the roles that fibroblasts play.  Future work will aim to identify effective drugs to target PKN2, which can be used in laboratory models of pancreatic and other cancers.