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Principal Investigator: Kazanietz, Marcelo G.
Institute Receiving Award University Of Pennsylvania
Location Philadelphia, PA
Grant Number R01ES026023
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2015 to 31 May 2021
DESCRIPTION (provided by applicant): This application focuses on the study of novel mechanisms involved in early events of lung carcinogenesis. Environmental carcinogens are major causative agents of lung cancer, as they induce genetic and epigenetic alterations that ultimately lead to the malignant transformation of lung epithelial cells. Oncogenic mutations in KRAS, a common alteration in non-small cell lung cancer (NSCLC), are induced in high frequency by lung carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and many other environmental carcinogens. It has been established that protein kinase C epsilon (PKCε), a mitogenic, pro-survival, and tumorigenic kinase, is up-regulated in epithelial cancers, including NSCLC. Studies from our laboratory revealed that PKCε is an essential mediator of tumor formation, invasiveness, and metastasis of NSCLC cells. More recently, we developed a mouse model for inducible lung-specific expression of KRas in a PKCε-deficient background (LSLK-rasG12D; PKCε-/-), and found that genetic ablation of the PKCε gene (PRKCE) markedly impairs the formation of tumors driven by the activated KRas allele. This suggests that PKCε is required for the initiation of KRas lung tumorigenesis. Moreover, in silico database analysis in KRAS mutated human lung adenocarcinomas revealed a significant association between high PKCε expression and short overall patient survival. Altogether, this led us to hypothesize that PKCε is a necessary mediator of the actions of lung carcinogens. In Specific Aim 1 we will examine if PKCε KO mice (in A/J genetic background) are resistant to the effects of lung carcinogens known to induce mutations in KRas, including the PAH benzo[a]pyrene (B[a]P) and urethane. We will examine if a pharmacological inhibitor of PKCε (εV1-2) inhibits the formation of lung tumors induced by these carcinogens or by an activated KRas allele. Mechanistic studies will be pursued to assess if carcinogens up-regulate PKCε in lung epithelial cells. In Specific Aim 2, we will use genetic and pharmacological approaches to determine if PKCε mediates the expansion of lung cancer progenitor cells (bronchioalveolar stem cells or BASCs) required for KRas- and carcinogen-induced tumorigenesis. To unambiguously establish a role for PKCε in initiation we will use gain-of-function approaches in cellular models as well as generate an inducible lung-specific transgenic mouse line for this kinase to determine if this leads to the formation of pre-malignant or malignant lung lesions. Finally, in Specific Aim 3 we will dissect the mechanistic basis for the functional interaction between KRas and PKCε in lung cancer, focusing on a) the analysis of elements of the Ras cascade, b) the identification of a PKCε gene signature and transcriptional networks regulated by this kinase in the context of KRas tumorigenesis, and c) the assessment of a potential role for PKCε in epithelial-mesenchymal transition (EMT), a process required for the acquisition of invasive capacity of lung cancer cells. Our studies should provide novel mechanistic insights into the molecular effects of environmental carcinogens as well as reveal important aspects of early events of lung carcinogenesis, thus impacting on our understanding of lung cancer etiology.
Science Code(s)/Area of Science(s) Primary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Frederick Tyson
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