New Approach to Pancreatic Cancer: Understanding the Role of Molecular Subtypes in Therapy
RBCT | January, 2025
A recent study led by the Robert Bosch Center for Tumor Diseases (RBCT) in Stuttgart has uncovered groundbreaking insights into the molecular mechanisms that control the identity of pancreatic cancer cells. These findings could have a direct impact on treatment strategies and outcomes for this aggressive form of cancer.
Multiplex immunofluorescence of patient-relevant subtype-specific markers helps delineate between classical and basal tumor cells, highlighting the high level of tumor heterogeneity present in PDAC patients
Pancreatic Cancer and Molecular Subtypes: Why They Matter
Pancreatic cancer is one of the deadliest forms of cancer. Each year, approximately 21,000 people in Germany are diagnosed with the disease, and most succumb within a year of diagnosis. In addition to late detection, the tumor’s remarkable ability to adapt to therapies poses a significant challenge.
One key discovery in pancreatic cancer research is the classification of tumors into two molecular subtypes: the classical and the basal subtype. Classical subtype tumors respond better to chemotherapy, while basal subtype tumors are more aggressive and associated with poorer prognoses. However, until now, little was known about the mechanisms that control the identity of these subtypes.
A New Perspective: Pharmacologically Influencing Cell Identity
The new study from RBCT reveals for the first time that the identity of pancreatic cancer cells can be pharmacologically altered through treatments that activate the glucocorticoid receptor (GR). Glucocorticoids like dexamethasone are already administered to nearly all pancreatic cancer patients, primarily to manage the side effects of chemotherapy.
The researchers found that activating GR can lead tumor cells to change their molecular identity. These changes could significantly influence how well the tumors respond to chemotherapy. “This work provides an important foundation for understanding the potential side effects and influence of glucocorticoids on pancreatic cancer therapy response,” explains Prof. Dr. Patrick Michl, Director of the Clinic for Gastroenterology at Heidelberg University. “However, the systemic effects of glucocorticoids are complex and may provide additional benefits for patients independent of their direct effects on tumor cell identity. Further studies are needed to distinguish these effects.”
New Avenues for Treatment Strategies
These findings open up new opportunities for developing treatment strategies that specifically alter the subtype identity of tumor cells to improve the efficacy of existing therapies. “We are just beginning to explore this avenue, but we hope these discoveries will lead to more personalized and effective treatments for pancreatic cancer in the future,” says Prof. Dr. Steven A. Johnsen, Scientific Director of RBCT and Honorary Professor at the University of Tübingen.
Collaborative Efforts Drive Progress
The study was conducted in close collaboration with the Mayo Clinic in the USA and the University Medical Center Göttingen. Prof. Dr. Elisabeth Hessmann, Head of the Clinical Research Group 5002 and co-author of the study, highlights the importance of teamwork: “We are delighted to have collaborated with Prof. Johnsen on this exciting project. This study makes a significant contribution with direct relevance to our ongoing work in KFO5002. We look forward to further collaborations to deepen our understanding of the molecular mechanisms that control subtype identity in pancreatic cancer.”
Publication:
Ekstrom TL, Rosok RM, Abdelrahman AM, Parassiadis C, Manjunath M, Dittrich MY, Wang X, Kutschat AP, Kanakan A, Rajput A, Schacherer N, Lukic T, Carlson DM, Thiel J, Kopp W, Stroebel P, Ellenrieder V, Gaedcke J, Dong M, Najafova Z, Truty MJ, Hessmann E, Johnsen SA. Glucocorticoid receptor suppresses GATA6-mediated RNA polymerase II pause release to modulate classical subtype identity in pancreatic cancer. Gut. 2025 Jan 30:gutjnl-2024-334374. doi: 10.1136/gutjnl-2024-334374. Epub ahead of print.