? DESCRIPTION (provided by applicant): Activating mutations in the K-Ras gene are the earliest and most common genetic alterations detected in human pancreatic cancer (PC) specimens and are associate with progression and metastasis. In genetically engineered mouse models (GEMMs) of PC, oncogenic K-Ras drives the formation of pancreatic intraepithelial neoplasia (PanIN lesions) and their progression to invasive PC. Oncogenic K-Ras has, at least, four effector pathways that play distinct roles in malignant transformation: MAPK pathway (mitogen-activated protein kinase), PI3K pathway (phosphoinositide 3-kinase), Ral-GDS (Ral guanine nucleotide dissociation stimulator), and Rac1 GTPase (Ras-related C3 botulinum toxin substrate 1). Among these effectors, the least well understood is the Rac1 pathway. Yet, this pathway has recently been shown to be critical for Ras-driven PC development. In transformation assays, Rac1 is required for transformation by the Ras oncogenes, and activated mutants of Rac1 can cooperate with the MAPK pathway to elicit malignant transformation. However, the specific mechanisms by which Rac1 promotes anchorage-independent growth and tumorigenicity are still unclear, so are the mechanisms responsible for its cooperation with the MAPK pathway. The objective of this proposal is to elucidate these mechanisms. Our central hypothesis is that the Rac1 and MAPK pathways act conjointly to control the expression/activity of proteins that play critical roles in integrating signals from cell-cell and ell-matrix interactions, most notably the YAP protein (Yes-associated protein 1). This hypothesis is based on preliminary data indicating that the inhibition of either Rac1 or MAPK pathway causes the degradation of the YAP protein. YAP is a transcriptional co-activator that controls genes involves in proliferation. The stability, location, and activity of YAP is controlled by signaling pathways involved in sensing cell-cell and cell-matrix interactions, such as the Hippo and Wnt pathways. In GEMMs of Ras-driven PC, YAP is required for the formation of PanIN lesions and their progression to invasive PC. In our telomerase-immortalized human pancreatic ductal cells, overexpressed YAP alone is sufficient to allow anchorage-independent growth. To test our central hypothesis and define the role of the Rac1 pathway in the initiation and progression of PC and its cooperation with the MAPK pathway, we propose three Specific Aims: Aim 1 will elucidate the mechanisms responsible for the transforming activity of Rac1 and its cooperation with the MAPK pathway; Aim 2 will evaluate Rac1 activity and YAP levels in human PC specimens and assess their pathobiological significance; and Aim 3 will delineate the cooperation and relative contributions of Rac1 and MAPK pathways in the initiation and progression of PC in GEMMs. Altogether, the proposed work will shed light on the mechanisms underlying Ras-driven carcinogenesis and reveal novel therapeutic targets, which could potentially be exploited for the treatment of pancreatic cancers and other Ras-driven malignancies.
|Effective start/end date||5/1/16 → 4/30/21|
- National Institutes of Health: $374,745.00