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Protein kinase C and lung carcinogenesis

蛋白激酶C与肺癌发生

基本信息

批准号：
10733467
负责人：
David Feldser
金额：
$ 67.44万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-06 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733467
关键词：
Actins Adenocarcinoma Cell Affect Animals Benzo(a)pyrene Biology Biosensor CRISPR/Cas technology Cancer Etiology Cancer Model Carcinogens Carcinoma Cell Separation Cells Cellular biology Cessation of life Clinical Clustered Regularly Interspaced Short Palindromic Repeats Competence Cytoskeletal Modeling Data Defect Development Dimensions Disease Environmental Carcinogens Epithelial Cells Epithelium Event Exposure to Extracellular Matrix Family Fluorescence Fluorescence Resonance Energy Transfer Gene Expression Genetic Genetically Engineered Mouse Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Hematopoietic Human In Vitro Invaded Joints KRAS oncogenesis KRAS2 gene KRASG12D Knock-out Link Lipids LoxP-flanked allele Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mass Spectrum Analysis Mediating Membrane Mesenchyme Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nude Mice Oncogenic Outcome Patients Peptide Hydrolases Phenotype Phorbol Esters Phosphorylation Phosphotransferases Play Positioning Attribute Production Protein Analysis Protein Deficiency Protein Kinase C Publishing RAS driven cancer Rationalization Receptor Protein-Tyrosine Kinases Recurrence Role Second Messenger Systems Series Signal Pathway Signal Transduction Stromal Cells Techniques Testing Tumor Promoters Work adenoma cancer cell cancer initiation candidate identification cell motility cell type experience in vivo innovation insight lung cancer cell lung carcinogenesis lung metastatic lung tumorigenesis malignant breast neoplasm member mouse model mutant neoplastic cell novel permissiveness protein activation protein kinase C epsilon protein kinase C kinase rac1 GTP-Binding Protein receptor screening targeted treatment tumor tumor initiation tumor microenvironment tumorigenesis

项目摘要

ABSTRACT Lung cancer is the leading cause of cancer-related deaths in the U.S., with ~236,700 new cases and ~130,200 deaths estimated for 2022. A joint effort by both PIs in this grant led to the identification of the oncogenic kinase protein kinase C epsilon (PKCe) as a key player in lung carcinogenesis. PKCe is aberrantly up-regulated in lung adenocarcinoma and is associated with poor outcome in patients specifically harboring KRAS mutations. Using genetically engineered mouse (GEM) models, we demonstrated that PKCe is required for both carcinogen- and Kras-driven lung tumorigenesis. In addition to this role in cancer initiation, our work established novel roles for PKCe in cellular events associated with late cancer stages. Indeed PKCe is a major player in lung cancer cell motility and invasion via activation of the small G-protein Rac1, linking this kinase to metastatic dissemination. That PKCe plays critical permissive roles first during adenoma initiation and then again later during the acquisition of metastatic competency highlights the functional complexities of the PKCe signaling events in lung cancer. Interestingly, CRISPR-mediated inactivation of PKCe in the initiating cell-of-origin does not significantly affect Kras- G12D-induced tumor development, leading us to hypothesize that PKCe does not strictly act in a tumor cell autonomous manner to permit oncogenic KRAS-mediated tumorigenesis. To test this hypothesis, in Aim 1 we will generate and characterize a series of GEM models to restrict genetic deletion of PKCe to either oncogenic Kras- expressing cancer cells or to diverse stromal cell types present in the tumor microenvironment, including non- cancerous epithelial, mesenchyme and hematopoietic cells. Gene expression studies on isolated cells using fluorescence-based lineage tracing techniques will provide significant mechanistic insights. In Aim 2, we will thoroughly dissect the mechanistic basis of motility/invasive signaling activation by PKCe. Our hypothesis is that PKCe activates Rac1-mediated formation of cell ruffles and motility in KRAS mutant lung cancer cells via Rac Guanine nucleotide Exchange Factors (Rac-GEFs). We will identify and characterize candidate Rac-GEFs as PKCe effectors responsible for this phenotype. In Aim 3, we will establish the involvement of PKCe and its effector Rac-GEFs for the development of metastatic lung cancer. We will use combined in vitro and in vivo approaches to pin down mechanistic defects in the metastatic cascade upon CRISPR-mediated deletion of PKCe and 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 its GEF effectors to lung adenocarcinoma metastasis, and identify relevant gene expression and signaling signatures contributing to this phenotype. Thus, by using innovative, state-of-the-art genetic and molecular approaches, our studies should reveal the vast multidimensional complexity of PKCe signaling in lung cancer development as well as underscore unappreciated mechanisms of carcinogen- and KRAS-mediated lung oncogenesis.

摘要