Pancreatic Disorders & Therapy
Open Access
ISSN: 2165-7092
+44 1478 350008
ISSN: 2165-7092
+44 1478 350008
Daniel R Principe and Paul J Grippo
University of Illinois College of Medicine, USA
University of Illinois at Chicago, USA
Scientific Tracks Abstracts: Pancreat Disord Ther
In early pancreatic carcinogenesis, TGF�?² acts as a tumor suppressor due to its growth-inhibitory effects in epithelial cells. However, in advanced disease, TGF�?² appears to promote tumor progression. Therefore, to better understand the contributions of TGF�?² signaling to pancreatic carcinogenesis, we generated mouse models of pancreatic cancer with either epithelial or systemic TGFBR deficiency in a background with pancreas-specific expression of mutant KRAS, which is nearly uniformly expressed in pancreatic cancer patients. We found that epithelial suppression of TGF�?² signals facilitated pancreatic tumorigenesis, whereas global loss of TGF�?² signaling protected against tumor development via inhibition of tumor-associated fibrosis, stromal TGF�?²1 production, and the resultant restoration of anti- tumor immune function. Similarly, TGFBR-deficient T cells resisted TGF�?²-induced inactivation ex vivo. Adoptive transfer of TGFBR-deficient CD8+ T cells into a more aggressive model of mutant Kras-induced disease led to enhanced infiltration and granzyme Bâ�?�?mediated destruction of developing tumors. These findings paralleled our observations in human patients, where TGF�?² expression correlated with increased fibrosis and associated negatively with expression of granzyme B. Collectively, our findings suggest that, despite opposing the proliferation of some epithelial cells, TGF�?² may promote pancreatic cancer development by affecting stromal and hematopoietic cell function. Therefore, the use of TGFBR inhibition to target components of the tumor microenvironment warrants consideration as a potential therapy for pancreatic cancer, particularly in patients who have genetic deletion of tumor-suppressive TGF�?² signals (i.e. DPC4/SMAD4) in the epithelium. While these patients are the most likely to benefit from TGFBR-inhibition therapy, there are many others in which TGF�?² signaling is perturbed despite the presence of all its necessary components. Upon further investigation, we found that under normal conditions, tumor suppressive TGF�?² signaling is highly dependent on the KRAS effector ERK. Yet this association was distinctly disrupted in human pancreatic cancer cells, and ERK opposes TGF�?²-induced cell cycle arrest. Our data also suggests that such patients with intact TGF�?² signaling may be highly susceptible to blockade of the MEK/ERK pathway, which restored normal tumor suppressive TGF�?² signals and reversed EMT in human pancreatic cancer cells. These two unique approaches are tailored to molecular cancer subtypes, and are currently in preclinical trials in both mice and a yet unpublished transgenic porcine model of pancreatic cancer.
Daniel R Principe is a Medical student at the University of Illinois- College of Medicine and previously completed a Master’s degree in Biomedical Engineering at Northwestern University and a Bachelor’s degree in Biology at Loyola University Chicago. His research focuses on the role of Transforming Growth Factor β (TGFβ) in pancreatic and colon cancers, Pigment Epithelium-Derived Factor (PEDF) in pancreatic cancer, and the development of large animal models of carcinogenesis.
Email: principe@illinois.edu