Pancreatic cancer has the highest mortality rate of all major cancers. Given that the disease is asymptomatic at early stages, pancreatic cancer is difficult to detect and easy to metastasize throughout the body.
In a new study published in the Journal of Clinical Investigation titled, “Antithrombin-binding heparan sulfate is ubiquitously expressed in epithelial cells and suppresses pancreatic tumorigenesis,” researchers from the Salk Institute and the University of California (UC) San Diego have identified a sugar, HSAT (antithrombin-binding heparan sulfate), as a potential therapeutic target for slowing tumor progression and metastasis in pancreatic ductal adenocarcinoma, the most common pancreatic cancer.
“We need to improve our understanding of the basic biology of pancreatic cancer if we want to one day prevent or cure it, and that’s what we’ve done here,” said Dannielle Engle, PhD, assistant professor at Salk and co-senior author of the study. “We discovered that HSAT is actually much more prevalent in the body than was previously understood, especially in cancer, and that it plays an important role in protecting against pancreatic cancer progression.”
Data collected from patient and mouse samples suggest that loss of HSAT expressed in pancreas cells prompts increased inflammation and a greater risk of metastasis. Boosting HSAT may slow the formation and spread of pancreatic cancer. Patients with higher pancreatic HSAT levels were found to have better survival rates. The study also found that HSAT was detectable in cancer patients’ plasma, making it potentially useful as a biomarker to track pancreatic cancer.
“Prior to our study, scientists thought HSAT was quite rare in the body. But we observed that pancreatic ductal adenocarcinoma cells express a high level of a key protein involved in forming HSAT, so we thought perhaps these tumors would express HSAT and set out to determine if that was true,” said Thomas Mandel Clausen, PhD, associate research scientist at UC San Diego and the study’s first author. “Very surprisingly, we found HSAT to be abundant in epithelial cells in multiple organs, and that indeed, HSAT was abundant in pancreatic ductal adenocarcinoma—especially in early stages of the disease.”
HSAT was present in both healthy pancreatic tissues and in pancreatic ductal adenocarcinoma. Importantly, patients with more HSAT in their tumors appeared to live longer, suggesting that the molecule may play a protective role in pancreatic cancer.
Results showed that pancreatic HSAT levels were especially high in early precancerous lesions and dipped as the cancer progressed. In mice growing tumors with no HSAT, pancreatic tumors were more inflamed, more resistant to cell death, and twice as likely to metastasize. Additional experiments showed that HSAT’s protective properties may stem from its regulation of the thrombin/PAR-1 axis, which mediates the interplay between blood coagulation and inflammation.
In addition to being a promising potential therapeutic target, HSAT may also serve as a useful biomarker of pancreatic cancer. The study demonstrated that HSAT can be detected in human plasma samples, and that HSAT levels are correlated with distinct tumor stages to allow HSAT to assist diagnosis of pancreatic cancer progression.
“The clinical application of our findings remains to be determined, but the implication is that patients expressing higher levels of HSAT may live longer,” said co-senior author Jeffrey Esko, PhD, distinguished professor and founding co-director of the Glycobiology Research and Training Center at UC San Diego. “If we can find ways to increase HSAT expression or screen for HSAT levels in patients, we could potentially alter the mortality outcomes for pancreatic cancer by catching it earlier and treating it more effectively.”
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