Sortilin may hold the key to combat pancreatic cancer more effectively

Novel study finds that levels of the neuroprotein sortilin are higher in pancreatic cancer cells than in normal pancreatic cells and sortilin may be a target for treatment, reports The American Journal of Pathology


Philadelphia, August 20, 2020

Pancreatic cancer has an extremely poor prognosis; it is the third most common cause of cancer deaths in the United States. In a novel study published in The American Journal of Pathology, published by Elsevier, scientists report the discovery of an increased level of the neuroprotein sortilin in pancreatic cancer cells that may open up the way to developing more effective treatment.

“There is currently no good therapy for pancreatic cancer,” explained lead investigator Hubert Hondermarck, PhD, School of Biomedical Sciences and Pharmacy and Hunter Medical Research Institute at the University of Newcastle, Australia. “What we need is a targeted therapy that could slow down the rapid progression of the disease to allow more time for chemotherapy and radiotherapy to be more effective."

The neuronal membrane protein sortilin is emerging as a key player in the regulation of neuronal viability and function, and there are increasing indications that it is involved in the deregulation of cancer cell viability. Sortilin is overexpressed in breast, lung, and thyroid cancer; it can promote cancer cell invasion in glioblastoma; and it participates in cancer cell adhesion and metastasis in colorectal cancer. However, its expression and impact in pancreatic cancer was not previously known.

In this study, investigators examined several pancreatic cancer cell lines alongside pancreatic ductal epithelial cells and established that sortilin expression was higher in the cancer cells, as demonstrated by Western blot and mass spectrometry. The increased sortilin level in pancreatic cancer cells was confirmed by immunohistochemistry in a series of 99 human pancreatic adenocarcinomas compared to 48 normal pancreatic tissues.

Furthermore, sortilin was found to contribute to pancreatic cancer invasion in vitro through potentially maintaining the focal adhesion kinase (FAK) signaling pathway. Researchers also found that sortilin levels were higher in female pancreatic cancer patients compared to males. “Our finding of higher sortilin expression in female patients suggests a possible regulation of sortilin gene expression by estrogen receptors, but further functional analyses are needed to confirm this hypothesis,” noted Dr. Hondermarck.


Pancreatic cancer cells in control (A) vs treatment by anti-sortilin targeting drug (B). When sortilin is targeted, pancreatic cancer cells partially lose attachment and cannot migrate. Scale bars = 50µm (Credit: Hubert Hondermarck’s Laboratory).

The main issue with pancreatic cancer is the local invasiveness of the tumor that leads to the destruction of the pancreas, rapidly causing death. This study showed that inhibiting sortilin with specific drugs or immunotherapy leads to a strong decrease in pancreatic cancer cell invasiveness. Therefore, specifically targeting sortilin is likely to complement and improve the efficacy of existing treatments. However, no statistically significant association was found between sortilin expression and pancreatic cancer aggressiveness. Therefore, although sortilin contributes to pancreatic cancer cell invasion, it is likely not the only factor involved.

“Together, these data reveal that sortilin contributes to pancreatic cancer invasion and is a potential therapeutic target,” commented Dr. Hondermarck. “This discovery may lead to the development of more efficient treatment against the disease.”

Pancreatic cancer is one of the most aggressive malignancies, with less than nine percent patient survival after five years. It is the seventh most common cause of cancer deaths worldwide and the third most common in the US. The most common type is pancreatic adenocarcinoma, which accounts for 90 percent of cases. Current therapeutic approaches include surgery, radiotherapy, and chemotherapy. Surgery is the most common treatment for early-stage pancreatic cancer, but it can be performed in less than twenty percent of patients. The main drug currently used to treat pancreatic cancer, gemcitabine, has only a limited therapeutic effect.

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Notes for editors
The article is “The Membrane Protein Sortilin Can Be Targeted to Inhibit Pancreatic Cancer Cell Invasion,” by Fangfang Gao, Nathan Griffin, Sam Faulkner, Xiang Li, Simon J. King, Phillip Jobling, Jim W. Denham, Chen Chen Jiang, and Hubert Hondermarck (https://doi.org/10.1016/j.ajpath.2020.05.018). It appears in The American Journal of Pathology, volume 190, issue 9 (September 2020) published by Elsevier.

It is openly available at https://ajp.amjpathol.org/article/S0002-9440(20)30289-3/fulltext.

The study was supported by the Maitland Appeal Cancer Committee, NSW, Australia (HH) and by a China Scholarship Council (FG).

Full text of the study is also available to credentialed journalists upon request; contact Eileen Leahy at +1 732 238 3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Hubert Hondermarck at hubert.hondermarck@newcastle.edu.au.

About The American Journal of Pathology
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. ajp.amjpathol.org

About Elsevier
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Media contacts
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Elsevier
+1 732 238 3628
ajpmedia@elsevier.com

Chhavi Chauhan, PhD, Director of Scientific Outreach
The American Journal of Pathology
+1 240 283 9724
cchauhan@asip.org