Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers, with less than 8% of patients surviving beyond five years after diagnosis. A key impediment to the treatment of PDAC is a highly desmoplastic tumor stroma. The abundance of non-neoplastic cells and extracellular matrix (ECM) in the stroma have been implicated in promoting aggressive tumor growth and inhibiting effective drug delivery. The ECM has long been thought to be primarily produced by stromal cells, including cancer associated fibroblasts (CAFs). However, our characterization of xenograft tumor models, in vitro co-cultures of CAFs and PDAC cells, and laser capture microdissected tumors has revealed that PDAC cells express a large proportion of the ECM. Furthermore, these studies revealed a CAF-dependent reprogramming of PDAC cells that allows for the expression of ECM components observed in tumors. We have previously demonstrated that the BET family of chromatin adaptors play key roles in the growth of PDAC tumors by regulating pathways in both PDAC and stromal cells. Building on this work, we have found the expression of the ECM in PDAC is broadly regulated by BET proteins. Among these BET-dependent genes are components of the hemidesmosome, a multiprotein complex that mediates signaling from the ECM to the cytoskeletal network of cells. This proposal will examine the mechanisms by which BET proteins mediate the CAF-dependent expression of the ECM in PDAC cells and define the biological role of Collagen XVII, a critical subunit of hemidesmosomes.
In Specific Aim 1 of this application, low passage PDAC cell lines and immortalized PDAC-derived CAF cultures will be utilized to examine the transcriptional mechanisms by which CAFs mediate the BET-dependent expression of the ECM- encoding genes in PDAC cells.
In Specific Aim 2, we will employ tumor models that temporally regulate the expression of Collagen XVII to define whether CAF-induced expression of Collagen XVII in PDAC cells contribute to PDAC tumor growth. Downstream Collagen XVII signaling pathways will be analyzed in tumors to elucidate the mechanisms by which this signaling contributes to tumor biology.
Over the past 40 years little progress has been made in the treatment of pancreatic cancer, the third leading cause of cancer-related deaths in the United States. This proposal characterizes the contribution of proteins involved in the communication of cancer cells with the tumor microenvironment. The insight gained from these studies will real novel mechanisms contributing to this highly chemoresistant disease and may provide new avenues for therapeutic intervention.
