Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significa...Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is generally a fatal disease with no efficacious treatment modalities.Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and che...Pancreatic ductal adenocarcinoma(PDAC)is generally a fatal disease with no efficacious treatment modalities.Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed.Here,we review the role of Yes-associated protein(YAP)and WW-domain-containing Transcriptional co-Activator with a PDZbinding motif(TAZ)in the development of PDAC.These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes.We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database(www.proteinatlas.org/pathology)that allows genome-wide exploration of the impact of individual proteins on survival outcomes.Multiple YAP/TEAD-regulated genes,including AJUBA,ANLN,AREG,ARHGAP29,AURKA,BUB1,CCND1,CDK6,CXCL5,EDN2,DKK1,FOSL1,FOXM1,HBEGF,IGFBP2,JAG1,NOTCH2,RHAMM,RRM2,SERP1,and ZWILCH,are associated with unfavorable survival of PDAC patients.Similarly,components of AP-1 that synergize with YAP(FOSL1),growth factors(TGFα,EPEG,and HBEGF),a specific integrin(ITGA2),heptahelical receptors(P2Y2R,GPR87)and an inhibitor of the Hippo pathway(MUC1),all of which stimulate YAP activity,are associated with unfavorable survival of PDAC patients.By contrast,YAP inhibitory pathways(STRAD/LKB-1/AMPK,PKA/LATS,and TSC/mTORC1)indicate a favorable prognosis.These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients.We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.展开更多
文摘Pancreatic ductal adenocarcinoma(PDAC) remains a deadly disease with no efficacious treatment options. PDAC incidence is projected to increase, which may be caused at least partially by the obesity epidemic. Significantly enhanced efforts to prevent or intercept this cancer are clearly warranted. Oncogenic KRAS mutations are recognized initiating events in PDAC development, however, they are not entirely sufficient for the development of fully invasive PDAC.Additional genetic alterations and/or environmental, nutritional, and metabolic signals, as present in obesity, type-2 diabetes mellitus, and inflammation, are required for full PDAC formation. We hypothesize that oncogenic KRAS increases the intensity and duration of the growth-promoting signaling network.Recent exciting studies from different laboratories indicate that the activity of the transcriptional co-activators Yes-associated protein(YAP) and WW-domaincontaining transcriptional co-activator with PDZ-binding motif(TAZ) play a critical role in the promotion and maintenance of PDAC operating as key downstream target of KRAS signaling. While initially thought to be primarily an effector of the tumor-suppressive Hippo pathway, more recent studies revealed that YAP/TAZ subcellular localization and co-transcriptional activity is regulated by multiple upstream signals. Overall, YAP has emerged as a central node of transcriptional convergence in growth-promoting signaling in PDAC cells. Indeed, YAP expression is an independent unfavorable prognostic marker for overall survival of PDAC. In what follows, we will review studies implicating YAP/TAZ in pancreatic cancer development and consider different approaches to target these transcriptional regulators.
基金E.R.is supported by NIH Grants P01CA163200,R01DK100405,and P30DK41301by a Department of Veterans Affair Grant 1I01BX001473+1 种基金funds from the endowed Ronald S.Hirschberg Chair of Pancreatic Cancer Research.G.E.is supported by P01CA163200funds from the Hirschberg Foundation of Pancreatic Cancer Research.The funders had no role in the preparation of the manuscript.
文摘Pancreatic ductal adenocarcinoma(PDAC)is generally a fatal disease with no efficacious treatment modalities.Elucidation of signaling mechanisms that will lead to the identification of novel targets for therapy and chemoprevention is urgently needed.Here,we review the role of Yes-associated protein(YAP)and WW-domain-containing Transcriptional co-Activator with a PDZbinding motif(TAZ)in the development of PDAC.These oncogenic proteins are at the center of a signaling network that involves multiple upstream signals and downstream YAP-regulated genes.We also discuss the clinical significance of the YAP signaling network in PDAC using a recently published interactive open-access database(www.proteinatlas.org/pathology)that allows genome-wide exploration of the impact of individual proteins on survival outcomes.Multiple YAP/TEAD-regulated genes,including AJUBA,ANLN,AREG,ARHGAP29,AURKA,BUB1,CCND1,CDK6,CXCL5,EDN2,DKK1,FOSL1,FOXM1,HBEGF,IGFBP2,JAG1,NOTCH2,RHAMM,RRM2,SERP1,and ZWILCH,are associated with unfavorable survival of PDAC patients.Similarly,components of AP-1 that synergize with YAP(FOSL1),growth factors(TGFα,EPEG,and HBEGF),a specific integrin(ITGA2),heptahelical receptors(P2Y2R,GPR87)and an inhibitor of the Hippo pathway(MUC1),all of which stimulate YAP activity,are associated with unfavorable survival of PDAC patients.By contrast,YAP inhibitory pathways(STRAD/LKB-1/AMPK,PKA/LATS,and TSC/mTORC1)indicate a favorable prognosis.These associations emphasize that the YAP signaling network correlates with poor survival of pancreatic cancer patients.We conclude that the YAP pathway is a major determinant of clinical aggressiveness in PDAC patients and a target for therapeutic and preventive strategies in this disease.
