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Principal Investigator: Kazanietz, Marcelo G.
Institute Receiving Award University Of Pennsylvania
Location Philadelphia, PA
Grant Number R56ES026023
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Sep 2015 to 31 Aug 2022
DESCRIPTION (provided by applicant): ABSTRACT KRAS mutations represent one of the most common early molecular events leading to oncogenic transformation in lung cancer. Environmental carcinogens such as benzo[a]pyrene (B[a]P) and other polycyclic aromatic hydrocarbons induce mutations in KRAS in cellular models and in vivo. Our studies identified the oncogenic kinase protein kinase C epsilon (PKCe) as a key player in cancer development. PKCe is aberrantly up-regulated in lung cancer and is associated with poor outcome in lung adenocarcinoma patients specifically harboring KRAS mutations. Using genetically engineered mice (GEM), we recently demonstrated the requirement of PKCe for Kras- driven lung tumorigenesis in vivo. In addition, B[a]P-induced lung carcinogenesis is abrogated in PKCe KO mice, a strong indication for the involvement of PKCe in oncogenic KRAS-mediated tumor initiation and in environmental carcinogenesis. Since CRISPR-mediated inactivation of PKCe in the initiating cell-of-origin does not significantly affect KRAS-G12D-induced tumor development, we hypothesize that this kinase may not strictly act in a tumor cell autonomous manner to permit oncogenic KRAS-mediated tumorigenesis in vivo. Beyond its role in cancer initiation, we also identified PKCe as an essential driver of cancer cell motility via the activation of the small GTPase Rac1 and the reorganization of the actin cytoskeleton into pro-motile ruffle protrusions. Thus, this kinase is implicated in multiple stages of lung cancer. In Aim 1, to elucidate a non-cancer cell-autonomous role for PKCe in oncogenic KRAS-mediated tumor development, we will generate and characterize a series of lung-specific KRAS-driven knock-in mouse models to restrict genetic deletion of PKCe to either oncogenic KRAS-expressing cells or microenvironmental cells, including non-cancerous epithelial cells, mesenchyme cells, and hematopoietic cells. Gene expression studies on isolated cells using fluorescence-based lineage tracing techniques will provide mechanistic insights in this context. In Aim 2, we will test the hypothesis that PKCe acts through the activation of Rac Guanine nucleotide Exchange Factors (Rac-GEFs) responsible for Rac1 activation to promote motility signaling in KRAS mutant lung cancer cells. We designed a screen to identify candidate Rac-GEFs responsible for this phenotype, which will be comprehensively characterized to dissect the mechanistic basis of Rac1 activation by PKCe. Also, a phospho-proteome signature driven by PKCe activation will be established using mass spectrometry. In Aim 3, we will establish the involvement of PKCe and Rac-GEF effectors in lung cancer metastasis. We will use combined in vitro and in vivo approaches to dissect mechanistic defects in the metastatic cascade upon CRISPR-mediated deletion of PKCe and the identified Rac-GEFs in lung adenocarcinoma cells. We will establish GEM models and use lentiviral CRISPR-based approaches to determine the permissive contribution of PKCe and Rac-GEFs to lung adenocarcinoma metastasis, and identify relevant gene expression and signaling signatures that contribute to the observed phenotypes. Our studies should reveal novel mechanisms of KRAS- driven lung oncogenesis and underline the vast functional complexity of PKCe biology in cancer development.
Science Code(s)/Area of Science(s) Primary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Frederick Tyson
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