Cholangiocarcinoma, a rare but highly aggressive cancer of the bile ducts, represents one of the toughest battles in the fight against cancer. This stealthy disease often goes undetected until it reaches an advanced stage, making it difficult to treat and leading to a poor prognosis for many patients. As the complex environment surrounding these tumors is further explored, hidden forces are being uncovered that allow cholangiocarcinoma to thrive and resist treatment. At the center of this discovery lies a protein that could hold the key to new, more effective therapies.
Recently, researchers at Albany Medical College, led by Professor Paul Higgins and in collaboration with Dr Ralf-Peter Czekay, Dr Hasan Aydin, Dr Rohan Samarakoon, Dr Nusret Subasi, Dr Hwajeong Lee, Craig Higgins and Stephen Higgins, reviewed current data to provide crucial insights into the role of SERPINE1 in cholangiocarcinoma (CCA) progression. Their study, published in Cells, sheds light on how the tumor microenvironment (TME) in CCA is determined by cancer-associated fibroblasts (CAFs) and how this, in turn, drives tumor progression and treatment resistance.
Researchers highlight that the desmoplastic reaction (a process involving the accumulation of a dense fibrotic matrix around the tumor) is a key factor in the poor prognosis and resistance to chemotherapy seen in cholangiocarcinoma. Within this fibrotic environment, CAFs play a central role by remodeling the extracellular matrix (ECM), promoting tumor cell survival, and fostering an environment conducive to cancer growth and spread.
SERPINE1, a gene encoding plasminogen activator inhibitor-1 (PAI-1), has been identified as a major player in this process. The study reveals that PAI-1 is heavily involved in remodelling the extracellular matrix, enhancing the fibrotic nature of the tumour. PAI-1 not only supports the physical structure of the tumour environment but also contributes to cancer cell invasion, metastasis and resistance to cell death. “The multifunctional role of PAI-1 in CCA progression makes it a potential therapeutic target, especially given its contribution to the aggressive and drug-resistant nature of these tumours,” Professor Higgins explained in a discussion of the findings.
The team explored the complex signaling pathways that facilitate the interaction between CAFs and tumor cells. The TGF-β pathway, in particular through its interaction with SERPINE1, stood out as a major driver of the desmoplastic reaction in CCA. This pathway not only improves the fibrotic environment, but also promotes pluripotency and plasticity of cancer cells, making them more adaptable and resistant to therapies.
In an effort to disrupt this damaging interaction, the study suggests that targeting PAI-1 or its associated pathways could prove beneficial. Experimental suppression of PAI-1 in cholangiocarcinoma cells led to a significant reduction in cell motility, indicating that inhibiting PAI-1 could slow or prevent the spread of cancer. “Our findings suggest that targeting PAI-1 in the tumour microenvironment could offer a new therapeutic approach to treating cholangiocarcinoma, particularly in cases where the tumour is resistant to conventional therapies,” Professor Higgins added.
This research by Professor Higgins and colleagues not only improves our understanding of the molecular mechanisms that drive cholangiocarcinoma, but also opens up new avenues for therapeutic intervention. By targeting components of the TME that facilitate tumour growth and resilience, their work offers the potential to improve outcomes for patients suffering from this challenging disease.
Journal reference
Czekay, R.-P., Higgins, C.E., Aydin, H.B., Samarakoon, R., Subasi, N.B., Higgins, S.P., Lee, H., & Higgins, P.J. (2024). “SERPINE1: a role in cholangiocarcinoma progression and a therapeutic target in the desmoplastic microenvironment”. Cells, 13, 796. DOI: https://doi.org/10.3390/cells13100796
About the authors
Paul J. Higgins He received his Ph.D. in molecular biology from New York University in 1976. He joined the faculty of Memorial Sloan-Kettering Cancer Center and Cornell University Medical College in 1977, where he was a member of the Cell Biology/Genetics and Molecular Biology/Virology programs. Dr. Higgins is currently Professor and Chairman of the Department of Regenerative and Cancer Cell Biology at Albany Medical College in Albany, New York. He was the founding Vice President of the Albany Research Institute (ARI) and currently serves on the ARI Board of Directors. He has served as chair of numerous National Institutes of Health and Department of Defense review panels, is a member of several federal and international study sections, and is the recipient of several prestigious awards, including the Moyer Prize and the 2008 Excellence in Molecular Medicine Award. Dr. Higgins serves on several journal editorial boards, has edited books on cancer biology, and has published over 300 peer-reviewed scientific articles.
Ralf Peter Czekay Dr. Czekay earned his PhD in physiology from the Max-Planck Institute for Molecular Physiology in Dortmund, Germany, in 1991. He completed his postdoctoral training at the University of California – San Diego and the Scripps Research Institute, La Jolla, California, under the mentorship of Drs. Marilyn Farquhar and David Loskutoff, respectively. During that period, Dr. Czekay developed a keen interest in the multilayered functions attributed to the serine proteinase inhibitor, plasminogen activator inhibitor type 1, PAI-1, especially with regard to tumor progression in human malignancies by regulating the proteolytic landscape in the tumor microenvironment. At that time, several research groups highlighted the unexpected clinical observation that elevated PAI-1 expression was, somewhat paradoxically, a strong marker of poor prognosis in breast cancer and shorter overall survival. Through his own research, he described a novel mechanism supporting this notion in which PAI-1 regulates tumor cell adhesion to extracellular matrix structures and overall cell motility by modulating the activity of integrins, a class of cell adhesion molecules. In 2004, Dr. Czekay joined the faculty of the Department of Regenerative and Cancer Cell Biology at Albany Medical College in Albany, New York, where he began and continues to expand his investigations of PAI-1 functions in prostate and ovarian cancer models. Currently, he is spearheading the formation of an integrative interdisciplinary research team with his colleague Dr. Paul Higgins and members of the AMC Department of Laboratory Medicine Pathology, to design novel therapeutic approaches targeting PAI-1 functions in human malignancies and pathological fibrotic environments. Dr. Czekay has published his research in peer-reviewed scientific journals and presented at numerous national and international scientific conferences.
Hasan Basri Aydin Dr. Aydin graduated from Istanbul University Cerrahpasa Faculty of Medicine in 2017, where he developed a strong interest in pathology. After briefly working in Turkey, Dr. Aydin moved to the United States and began his pathology residency at Albany Medical Center in 2021, focusing on gastrointestinal, hepatic, and pancreatobiliary pathology. This focus led to his acceptance into a gastrointestinal pathology fellowship at Northwell Health. Dr. Aydin’s research interests have led him to contribute to numerous publications focusing on tumors of the digestive system and benign and malignant conditions of the liver and pancreas. Dr. Aydin is a member of the New York Pathology Society (NYPS), the Rodger C. Haggitt Gastrointestinal Pathology Society (GIPS), the Hans Popper Hepatopathology Society, and the Pancreatobiliary Pathology Society. He has participated in national-level pathology conferences as a presenter, including the annual meetings of USCAP, ASCP, and CAP. Dr. Aydin’s latest manuscript, titled “A metastatic AFP-producing carcinoma of gastric origin masquerading as hepatocellular carcinoma on liver biopsy,” has been published as the GIPS Case of the Month for July 2024.
Lee Hwajeong is a Professor of Pathology and Laboratory Medicine and Vice Chair of Academic Affairs in the Department of Laboratory Medicine Pathology at Albany Medical College in Albany, New York. She completed her medical education at Yonsei University College of Medicine in Seoul, South Korea, and completed her residency in combined anatomic and clinical pathology at Henry Ford Hospital in Detroit, followed by a fellowship in oncologic surgical pathology and a fellowship in subspecialty pathology (gastrointestinal, liver, and pancreatobiliary pathology) at Memorial Sloan Kettering Cancer Center in New York and the Cleveland Clinic in Cleveland, respectively. Her research interests focus on the identification of morphologic and immunohistochemical biomarkers that may aid in the diagnosis, prognosis, and therapy of various neoplastic and non-neoplastic conditions of the gastrointestinal tract, liver, and pancreatobiliary tract.
Subasio by Nusret Bekir Dr. Subasi is a postgraduate pathology resident (PGY)-1 at Albany Medical Center in Albany, New York. After graduating from Gaziantep University School of Medicine in Turkey in 2018, Dr. Subasi has had several clinical and research experiences in pathology prior to his current position. He is excited about potential future collaborative and translational research projects.
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