The goals of this project are to elucidate protein kinase C (PKC) signaling mechanisms that contribute to lung cancer initiation and maintenance and translate these mechanistic insights into better prognostic and treatment strategies. We recently identified the atypical PKCi gene PRKCI as a human oncogene in the lung. Furthermore, we find that the mouse PKCi gene Prkci is required for the very earliest steps of lung tumorigenesis induced by oncogenic Kras in vivo. Specifically, Prkci is necessary for Kras-mediated transformation of bronchio-alveolar stem cells (BASCs), the putative cell of origin of Kras-mediated lung tumorigenesis. Genetic disruption of Prkci, or treatment with the PKC? inhibitor aurothiomalate (ATM), blocks Kras-mediated expansion and morphological transformation of BASC in vitro and in vivo, and lung tumor growth in vivo. Preliminary results suggest that Kras-, Prkci-mediated expansion of BASCs involves induction of the polycomb gene Bmi1. Bmi1 is an epigenetic chromatin modifier/transcriptional regulator implicated in cancer stem cell identity and self-renewal. Like Prkci, Bmi1 is necessary for Kras-mediated BASC expansion and lung tumorigenesis. Based on these preliminary data, we hypothesize that Prkci drives Kras-mediated BASC transformation and lung tumorigenesis, at least in part, through activation of the Bmi1 signaling pathway. We further hypothesize that a similar PKCi-Bmi1 signaling axis plays a critical role in the maintenance, expansion and tumorigenic potential of human lung cancer stem cells. Finally, we hypothesize that ATM will effectively inhibit the self-renewal and tumorigenic potential of human lung cancer stem cells. We will test these hypotheses through completion of two interrelated specific aims.
In Aim 1 we will assess the role of the PKCi-Par6-Ect2-Rac1 signaling axis in BASC transformation and dissect the mechanism of crosstalk between PKCi and Bmi1 signaling in these cells.
In Aim 2 we will determine the role of PKCi and Bmi1 signaling in the self-renewal and tumor initiating activity of lung cancer stem cells. We will develop and characterize a panel of lung cancer stem cell lines from primary lung tumors. Completion of these studies will provide important new mechanistic insight into oncogenic PKCi signaling in putative lung cancer stem cells, enhance our understanding of Kras-mediated lung tumorigenesis, and assess the efficacy of a novel therapeutic agent that targets a critical oncogenic pathway in lung cancer stem cells. These studies have important implications for PKCi as a therapeutic target and for the use of ATM as a novel therapeutic for the treatment of lung cancer.

Public Health Relevance

Lung cancer is the number one cause of cancer death in the United States. Protein kinase Ci (PKCi) is an oncogene, prognostic marker and therapeutic target in lung cancer. This project will elucidate PKCi signaling mechanisms that drive lung cancer stem cell growth and tumor-initiating activity, and determine the efficacy of a novel PKCi inhibitor, aurothiomalate, to block lung cancer stem cell growth and tumorigenicity. Finally, this project will generate novel lung cancer stem cell resources from human lung cancer patients. These tissue resources will be invaluable in the assessment of novel therapeutics targeting these deadly cells.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Molecular Oncogenesis Study Section (MONC)
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Ogunbiyi, Peter
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Mayo Clinic Jacksonville
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Fields, Alan P; Ali, Syed A; Justilien, Verline et al. (2017) Targeting oncogenic protein kinase C? for treatment of mutant KRAS LADC. Small GTPases 8:58-64
Justilien, Verline; Ali, Syed A; Jamieson, Lee et al. (2017) Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma. Cancer Cell 31:256-269
Fields, Alan P; Justilien, Verline; Murray, Nicole R (2016) The chromosome 3q26 OncCassette: A multigenic driver of human cancer. Adv Biol Regul 60:47-63
Ali, Syed A; Justilien, Verline; Jamieson, Lee et al. (2016) Protein Kinase C? Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma. Cancer Cell 29:367-378
Justilien, Verline; Fields, Alan P (2015) Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res 21:505-13
Justilien, Verline; Walsh, Michael P; Ali, Syed A et al. (2014) The PRKCI and SOX2 oncogenes are coamplified and cooperate to activate Hedgehog signaling in lung squamous cell carcinoma. Cancer Cell 25:139-51
Justilien, Verline; Regala, Roderick P; Tseng, I-Chu et al. (2012) Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS One 7:e35040
Justilien, Verline; Jameison, Lee; Der, Channing J et al. (2011) Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation. J Biol Chem 286:8149-57
Murray, Nicole R; Kalari, Krishna R; Fields, Alan P (2011) Protein kinase C? expression and oncogenic signaling mechanisms in cancer. J Cell Physiol 226:879-87
Regala, Roderick P; Justilien, Verline; Walsh, Michael P et al. (2011) Matrix metalloproteinase-10 promotes Kras-mediated bronchio-alveolar stem cell expansion and lung cancer formation. PLoS One 6:e26439

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