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.

New Druggable Target for Pancreatic Cancer Discovered - Medicine Innovates

About the author

Dr Angus James Cameron, PhD

Senior Lecturer

He joined Barts Cancer Institute in 2013 as an Early Career Researcher in the Centre for Tumour Biology and was promoted to Senior Lecturer in 2018.

The targeting of protein kinases represents an opportunity and challenge in cancer treatment. Some 2% of transcribed genes are kinases, many implicated in tumorigenesis and all potentially druggable.

My research encompasses various cancer associated kinases, including PKC, PKN, mTOR and EGFR family tyrosine kinases. In particular, my work on PKC and the HER family of tyrosine kinase growth factor receptors has revealed that inhibitors can have surprising allosteric effects on kinase function with significant implications for therapy.

My group is currently examining the role of the PKN kinases in malignant progression. PKN kinases are effectors of Rho family GTPases, regulating cell shape, adhesion and motility. Our studies on the role for PKN family members in mammalian development has provided significant insight; we have described a key non-redundant role for the PKN2 isoform in the regulation of embryo morphogenesis, cell proliferation and migration; phenotypes critically linked to cancer progression (Cell Reports 2016).

The PKN kinases are dramatically upregulated in many cancers and high expression has been correlated with metastatic disease – the spread of cancer around the body. Our current studies focus on the stromal roles for the PKN kinases in pancreatic and breast cancer, supported by the novel roles we have discovered for PKN during development. The ultimate goal of this research is to assess whether these kinases represent a significant cancer drug target.


Elizabeth R. Murray, Shinelle Menezes, Jack C. Henry, Josie L. Williams, Lorena Alba-Castellón. Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion. Cell Reports,  Volume 38, Issue 4, 110227,  2022

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