Abstract A30: AKT activation as a mechanism of escape from TGF{beta}-mediated lethal EMT

Frequent inactivation of transforming growth factor β (TGFβ) pathway core components in pancreatic ductal adenocarcinoma (PDA), especially the transcription factor SMAD4, suggests that TGFβ signaling is tumor suppressive in the pancreas. Yet, 50% of PDA retains an intact core TGFβ pathway, suggesting that there are mechanisms by which these tumors escape TGFβ-mediated tumor suppression. In unpublished work, we have delineated a mechanism for TGFβ-mediated tumor suppression via a lethal epithelial-mesenchymal transition (EMT). Based on clinical and in vitro evidence that AKT activation may suppress the lethal EMT response to TGFβ, we are investigating the role of AKT signaling in directly interfering with TGFβ-mediated tumor suppression. We have taken two major approaches: (1) to test the concept that AKT inhibition may reactivate TGFβ-mediated tumor suppression, we are chemically inhibiting AKT in PDA mouse models competent and deficient in TGFβ signaling, and (2) to understand the mechanism of AKT-TGFβ crosstalk in PDA progression, we are performing RNAseq-based gene expression profiling of SMAD4-restored PDA cell lines. We have found that in vitro, AKT signaling determines whether TGFβ induces apoptosis in SMAD4-restored PDA cell lines, and by gene expression analysis, we have identified a group of genes that are differentially regulated by TGFβ in the presence and absence of AKT signaling. Furthermore, we hav...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Pediatric Cancers and Development: Poster Presentations - Proffered Abstracts Source Type: research