Recent evidence indicates that invasion of human pancreatic ductal adenocarcinoma (PDAC) cells in 3D collagen depends on G α13, a member of the G12 family of heterotrimeric G proteins, and can be reversed by the collagen-binding protein discoidin domain receptor 1 (DDR1). The long-term goal is to contribute to the development of novel mechanism-based targeted therapies for the treatment of PDAC. The main objective in this application is to determine how Gα13 contributes to PDAC progression in vivo. The central hypothesis is that Gα13 enhances PDAC progression by disrupting DDR1-mediated cell-cell adhesion and by activating YAP1 signaling. A second ypothesis is that Gα13 enhances inflammation that is present in PDAC tumors. These hypotheses are based on extensive preliminary data demonstrating that Gα13 knockdown decreases invasion in 3D collagen, decreases YAP1 signaling, and enhances E-cadherin-mediated cell-cell adhesion. In addition, loss of the polarity protein Par3, which can function downstream of DDR1, enhances YAP1 signaling and promotes invasion of PDAC cells in 3D collagen. Moreover, Gα13 in PDAC cells regulates expression of stem cell factor (SCF), which is known to mediate mast cell migration. The rationale for the proposed research is that a determination of the effect and underlying mechanism of Gα13 in PDAC progression in vivo is likely to provide strong justification for the continued development of Gα13 and its downstream effectors as targets for novel anti-PDAC therapy. Three specific aims are proposed: 1) Determine the role of Gα13 in PDAC progression in vivo; 2) Determine the role of Gα13 in mediating PDAC inflammation in vivo; and 3) Determine the mechanism by which DDR1 counteracts Gα13 in PDAC cells in vivo. Under the first aim, the effects of knocking out Gα13 on tumor progression will be evaluated in transgenic models, in established tumors in an orthotopic model, in 3D acinar cultures, and in human pancreatic cancer organoids. Also, the role of YAP1 in Gα13-mediated PDAC progression will be assessed. For the second aim, the mechanism by which Gα13 expression in PDAC cells regulates mast cell migration will be determined. In addition, the extent to which Gα13modulates inflammation in transgenic mouse models will be evaluated. In the third aim, the role of Par3 in mediating tumor progression in transgenic mouse models, in 3D acinar cultures, and in human pancreatic cancer organoids will be evaluated. The extent to which Par3 functions downstream of DDR1 to attenuate the effects of Gα13 on PDAC progression will also be determined. The research proposed is innovative because it utilizes complex models of pancreatic cancer, including 3D acinar cultures, human pancreatic cancer organoids, and transgenic and orthotopic mouse models, to delineate the role of Gα13 and Par3 in PDAC progression. This proposed research is significant because it will provide a mechanistic determination of the role of Gα13 in mediating PDAC tumor progression and metastasis, and also PDAC inflammation, subsequently creating new opportunities for the development of innovative therapies to treat PDAC patients.
|Effective start/end date||4/1/18 → 3/31/24|
- National Cancer Institute (5R01CA217907-05)
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