Abstract A042: Opioids drive extracellular matrix remodeling in the pancreatic tumor microenvironment

Abstract

Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 13.3%. The disease is characterized by a dense, desmoplastic stroma comprised of extracellular matrix (ECM) proteins produced by cancer-associated fibroblasts (CAFs). This dense ECM has profound impacts on tumor development and therapy response. In a study conducted by the Pancreatic Cancer Action Network, 93% of pancreatic cancer patients reported experiencing pain, with 83% reporting their pain as moderate-to-severe. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids across all stages of disease. Opioids, which predominantly signal through the mu-opioid receptor (MOR), relieve pain through the hyperpolarization of neurons and inhibition of pain transmission in the central nervous system. However, opioids have peripheral effects outside of their analgesic function, such as the commonly experienced opioid-induced side effect of constipation. Importantly, most studies investigating opioids and patient outcomes have correlated opioid use with worsened survival in various cancer types including pancreatic cancer. Despite the wide use of opioids in pancreatic cancer and their association with worse outcome, little is known about how opioids impact tumorigenesis, the ECM, and therapy response. We have discovered that morphine increases expression of collagens and other ECM-related genes in a murine model of pancreatic cancer, and that both pharmacological inhibition and knockdown of MOR in CAFs in vitro reduces RNA and protein expression of type 1a and type 3a collagens. Further, tumors from mice treated with morphine exhibited increased collagen bundling and maturation and were more poorly differentiated, features associated with poor outcome. We developed an ECM-related morphine-induced gene signature which significantly correlated with the basal subtype, as well as poor overall and disease-free survival in pancreatic cancer and several other tumor types. Finally, we have discovered that endogenous opioid peptide precursors are expressed in pancreatic tumor cells and CAFs, capable of driving CAF collagen expression, supporting a potential role for endogenous opioid signaling in regulating collagen and the ECM even in the absence of prescription opioids. Thus, we propose that exogenous and endogenous opioids act on MOR in CAFs to promote ECM remodeling in the pancreatic tumor microenvironment, resulting in more aggressive tumors and worse prognosis. Citation Format: Kathryn E. Maraszek, Hunter D. Reavis, Arwen A. Tisdale, Xiaozhuo Liu, Eduardo Cortes Gomez, Aleksandr Dolskii, Caneta Brown, Janusz Franco-Barraza, Edna Cukierman, Michael E. Feigin. Opioids drive extracellular matrix remodeling in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3): nr A042.