The prognosis of patients with pancreatic ductal adenocarcinomas (PDAC) remains dismal with a five-year survival of less than 5%. It is hoped that understanding the molecular mechanisms contributing to the invasive nature and the resistance of PDAC to chemotherapy will provide the bases for new molecular-targeted therapies. To this end, we show here for the first time that there is a dynamic interaction between TGF? and STAT3 activities, which contribute to the invasiveness of PDAC and that targeting these pathways may block invasion and enhance sensitivity to chemotherapy. One of the hallmarks of tumor progression is a switch of TGF? signaling from tumor suppression to tumor promotion. This seemingly paradoxical aspect of TGF? signaling is under extensive investigation. TGF? signals through both Smad-dependent and Smad-independent pathways. Our studies indicate that anti-invasive functions of TGF? in PDAC require Smad signaling. However, more than half of PDACs possess allelic deletion or inactivating mutations of the Smad4 gene. Moreover, in tumor cells that possess intact Smad components, oncogenic signals can attenuate Smad signaling or alter TGF? transcriptional responses to favor tumor promotion. We found that STAT3 was constitutively activated in PDAC and that there is reciprocal negative regulation between Smads and STAT3 pathways. In Smad4 intact cells, knocking down STAT3 enhanced Smad signaling and inhibited TGF? mediated motility and invasion. In Smad4 deficient PDAC cells, STAT3 activity cooperates with and is required for TGF? induced motility and invasion. Our preliminary results also suggest that that STAT3 remains activated in PDAC treated with Gemcitabine and EGFR-kinase inhibitors. Blocking TGF?/STAT3 axis prevented invasion and enhanced sensitivity to Gemcitabine. Our central hypothesis is that oncogenic alterations in PDAC cause an aberrant TGF?/STAT3 axis that is functionally linked to both invasiveness and resistance to chemotherapy. We will test this hypothesis by completing the following aims.
Aim 1. Determine the role of STAT3 in regulating Smad signaling and determine whether this influences tumor progression in PDAC.
Aim 2. Determine the role that cross talk between STAT3 activity and Smad4-independent TGF? signaling plays in tumor progression.
Aim 3. Determine whether targeting the TGF?/STAT3 axis improves therapy of PDAC. The completion of these studies will further define the molecular and functional relationship between TGF? and STAT3 and the role these interaction play in the invasiveness and response of PDAC to conventional therapies. Ultimately, a successful outcome of these studies may provide the bases for new clinical trials.
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States with a five-year survival rate of less than 5%. The studies proposed in the current application will investigate the role that interaction of TGF2 and STAT3 play in the invasive properties and resistance of pancreatic cancer to chemotherapy. These studies include pre-clinical assessment for targeting the TGF?/STAT3 axis and if successful should provide support for clinical trials.
|Zhao, Shujie; Chen, Chen; Chang, Katherine et al. (2016) CD44 Expression Level and Isoform Contributes to Pancreatic Cancer Cell Plasticity, Invasiveness, and Response to Therapy. Clin Cancer Res 22:5592-5604|
|Chang, Katherine; Karnad, Anand; Zhao, Shujie et al. (2015) Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets. Oncotarget 6:3507-18|
|Gong, Jingjing; Xie, Jianping; Bedolla, Roble et al. (2014) Combined targeting of STAT3/NF-?B/COX-2/EP4 for effective management of pancreatic cancer. Clin Cancer Res 20:1259-73|
|Bera, Alakesh; VenkataSubbaRao, Kolaparthi; Manoharan, Muthu Saravanan et al. (2014) A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer. PLoS One 9:e106343|
|Zhao, S; Cao, L; Freeman, J W (2013) Knockdown of RON receptor kinase delays but does not prevent tumor progression while enhancing HGF/MET signaling in pancreatic cancer cell lines. Oncogenesis 2:e76|
|Bera, Alakesh; Zhao, Shujie; Cao, Lin et al. (2013) Oncogenic K-Ras and loss of Smad4 mediate invasion by activating an EGFR/NF-?B Axis that induces expression of MMP9 and uPA in human pancreas progenitor cells. PLoS One 8:e82282|
|Venkatasubbarao, Kolaparthi; Peterson, Lindsay; Zhao, Shujie et al. (2013) Inhibiting signal transducer and activator of transcription-3 increases response to gemcitabine and delays progression of pancreatic cancer. Mol Cancer 12:104|
|Thangasamy, Amalraj; Rogge, Jessica; Krishnegowda, Naveen K et al. (2011) Novel function of transcription factor Nrf2 as an inhibitor of RON tyrosine kinase receptor-mediated cancer cell invasion. J Biol Chem 286:32115-22|
|Zhao, Shujie; Wang, Yubao; Cao, Lin et al. (2010) Expression of oncogenic K-ras and loss of Smad4 cooperate to induce the expression of EGFR and to promote invasion of immortalized human pancreas ductal cells. Int J Cancer 127:2076-87|
|Zhao, Shujie; Venkatasubbarao, Kolaparthi; Lazor, Jillian W et al. (2008) Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res 68:4221-8|
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