Mechanisms of Escape from TGFβ Tumor Suppression in the Pancreas

Abstract public domain (NIH RePORTER)

DESCRIPTION (provided by applicant) Mechanisms of Escape from TGFβ Tumor Suppression in the Pancreas With a five-year survival rate of less than six percent, pancreatic ductal adenocarcinoma (PDAC) is projected to become the second most common cause of cancer deaths by 2030 in the United States-unless progress is made in preventing or treating it. Genetic and histologic evidence from human PDAC suggest that the transforming growth factor β (TGFβ) pathway is tumor suppressive in the early stages of PDAC development. The goal of this project is to better understand the conditions under which TGFβ mediates tumor suppression in the pancreas and to identify targetable signaling pathways that cause failure of TGFβ tumor suppression. We have delineated a mechanism by which TGFβ induces conflicting differentiation programs in premalignant pancreatic cells, resulting in apoptosis. This mechanism provides a selective pressure favoring the inactivation of the TGFβ pathway, particularly via SMAD4 deletion and mutation. Half of PDACs retain a competent TGFβ pathway, however, suggesting that there are additional ways for pancreatic cells to circumvent TGFβ-mediated apoptosis. Our preliminary evidence suggests that up-regulation of AKT signaling is one way by which cells can bypass TGFβ-mediated tumor suppression. In Aim 1, I plan to (a) use mouse models to explore the possibility of exploiting the interaction between AKT and TGFβ signaling to inform treatment of TGFβ-competent PDAC and (b) to define a mechanism for the crosstalk between the two pathways using gene expression profiling. In Aim 2, I seek to (a) use next generation sequencing of mouse models to identify additional pathways that allow cells to overcome TGFβ-mediated tumor suppression and (b) functionally characterize the interaction of an identified pathway using an embryonic stem cell-based mouse model. Through these studies, I hope to provide insight into the interplay of the signaling networks that drive the progression of pancreatic cancer and generate a better understanding of targetable vulnerabilities in this cancer type.

Public health relevance public domain (NIH RePORTER)

PUBLIC HEALTH RELEVANCE: Mechanisms of Escape from TGFβ Tumor Suppression in the Pancreas Understanding the signaling pathways that determine the success of TGFβ-mediated tumor suppression in the premalignant pancreas will provide insights into the progression of pancreatic cancer. With a better grasp of the mechanisms of signal crosstalk in pancreatic cancer progression, we will be able to design more rational treatment strategies.