Lung cancer is the leading cause of cancer deaths worldwide. It is estimated that in 2006, more than 163,500 people, in the US alone, will die from this disease. The reasons for the high death rate are detection and diagnosis at advanced stages and a lack of efficient treatments for advanced lung cancer. To identify treatments for advanced stage cancers, we must first understand the molecular mechanisms underlying the disease if we are to identify appropriate targets for the development of therapeutics. One the most common mutations found in lung adenocarcinoma are activating mutations of the K-ras gene, found in 20-30% of all lung adenocarcinomas. We have used this knowledge to develop a mouse model of lung adenocarcinoma that closely recapitulates the human form of the disease. Given the emerging data implicating the small G-proteins of the Rac family in Ras-induced tumorigenesis we examined the potential function of Rac1 as an oncogene and the requirement for Rac1 downstream of K-ras in lung adenocarcinoma. The Rac small G-proteins are regulators of diverse signaling pathways including those mediating cytoskeleton reorganization, gene expression, endocytosis and cell proliferation and survival. The deregulation of these pathways is a reoccurring theme in tumorigenesis. Our findings indicate that a naturally occurring splice form of Rac1 is upregulated in a significant percentage of human lung adenocarcinomas and that Rac1 is required for K- ras induced lung tumors. Furthermore, while Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. Thus, there is a synthetic requirement for Rac1 function in cells expressing oncogenic K-ras. These studies will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that loss of Rac1 is """"""""lethal"""""""" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras-mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells.
The studies proposed will shed light on the process of tumor initiation and progression and enhance our understanding of the molecular pathways involved in lung cancer. The finding that Rac1b might function as an oncogene and that loss of Rac1 is """"""""lethal"""""""" in the context of activated K-ras raises the possibility that targeting Rac1 in Ras- mutated tumors would be therapeutically beneficial with, perhaps, limited toxicity towards normal cells. Given the prevalence of Ras mutations in human cancer these finds could potentially have an impact on a broad spectrum of cancers.
|Moleirinho, Susana; Hoxha, Sany; Mandati, Vinay et al. (2017) Regulation of localization and function of the transcriptional co-activator YAP by angiomotin. Elife 6:|
|Guerrant, William; Kota, Smitha; Troutman, Scott et al. (2016) YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis. Cancer Res 76:3507-19|
|Troutman, Scott; Moleirinho, Susana; Kota, Smitha et al. (2016) Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1. Oncotarget 7:54515-54525|
|Moleirinho, Susana; Guerrant, William; Kissil, Joseph L (2014) The Angiomotins--from discovery to function. FEBS Lett 588:2693-703|
|Yi, Chunling; Shen, Zhewei; Stemmer-Rachamimov, Anat et al. (2013) The p130 isoform of angiomotin is required for Yap-mediated hepatic epithelial cell proliferation and tumorigenesis. Sci Signal 6:ra77|
|Avila, Jacqueline L; Kissil, Joseph L (2013) Notch signaling in pancreatic cancer: oncogene or tumor suppressor? Trends Mol Med 19:320-7|
|Licciulli, Silvia; Maksimoska, Jasna; Zhou, Chun et al. (2013) FRAX597, a small molecule inhibitor of the p21-activated kinases, inhibits tumorigenesis of neurofibromatosis type 2 (NF2)-associated Schwannomas. J Biol Chem 288:29105-14|
|Zhou, C; Licciulli, S; Avila, J L et al. (2013) The Rac1 splice form Rac1b promotes K-ras-induced lung tumorigenesis. Oncogene 32:903-9|
|Licciulli, Silvia; Avila, Jacqueline L; Hanlon, Linda et al. (2013) Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Res 73:5974-84|
|Avila, Jacqueline L; Troutman, Scott; Durham, Amy et al. (2012) Notch1 is not required for acinar-to-ductal metaplasia in a model of Kras-induced pancreatic ductal adenocarcinoma. PLoS One 7:e52133|
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