EXCEED THE SPACE PROVIDED. Cancer is a disease in which growth stimulatory pathways are excessively active. Considerable experimental evidence implicates Ras proteins as essential components of growth stimulatory signal transduction pathways. Moreover, oncogenic forms of Ras are expressed in a variety of human cancers with a strikingly high prevalance (>90%) in pancreatic cancer. The long term objective of this research project is to define the precise role that oncogenic Ras plays in tumorigene'sis. The combined efforts of many groups, including our own, have led to the identification of multiple effector pathways that are controlled by Ras. The goal of the studies proposed in this application is to characterize the cellular responses that are triggered by Ras-dependent effector pathways, and to assess the relevance of these responses to tumor initiation and progressioin.
Our specific aims are as follows: ; 1. To identify effector pathways that couple the oncogenic activation of Ras to the metastatic phenotype. 2. To define the mechanisms by which Ras controls tumor-stroma interactions. 3. To delineate the function of Ras in pancreatic tumorigenesis. Collectively, the studies to be pursued within the framework of this proposal will advance our mechanistic understanding of growth control perturbation that are critical for oncogenic transformation and, as such, may lead to the identification of new modalities for therapeutic intervention.
| Grabocka, Elda; Commisso, Cosimo; Bar-Sagi, Dafna (2015) Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response. Clin Cancer Res 21:1243-7 |
| Grabocka, Elda; Pylayeva-Gupta, Yuliya; Jones, Mathew J K et al. (2014) Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25:243-56 |
| Pylayeva-Gupta, Yuliya; Lee, Kyoung Eun; Bar-Sagi, Dafna (2013) Microdissection and culture of murine pancreatic ductal epithelial cells. Methods Mol Biol 980:267-79 |
| Jeng, Hao-Hsuan; Taylor, Laura J; Bar-Sagi, Dafna (2012) Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun 3:1168 |
| Mallen-St Clair, Jon; Soydaner-Azeloglu, Rengin; Lee, Kyoung Eun et al. (2012) EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev 26:439-44 |
| Ochi, Atsuo; Nguyen, Andrew H; Bedrosian, Andrea S et al. (2012) MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 209:1671-87 |
| Pylayeva-Gupta, Yuliya; Lee, Kyoung Eun; Hajdu, Cristina H et al. (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21:836-47 |
| Zheng, Ze-Yi; Xu, Lizhong; Bar-Sagi, Dafna et al. (2012) Escorting Ras. Small GTPases 3:236-9 |
| Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761-74 |
| Lee, Kyoung Eun; Bar-Sagi, Dafna (2010) Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 18:448-58 |
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