In Vivo Tagging of Lung Epithelial Cells to Define the Early Steps of Tumor Cell Dissemination.

摘要

To understand the early events that accompany invasive behavior in vivo, we proposed to develop a lineage-labeling system to detect and isolate cells of lung epithelial origin during tumor progression in a mouse model of lung cancer. A mouse model of lung cancer with metastasis [LSL-KrasG12D/Lkb1L/L mice] was interbred with Nkx2.1-CreERT2 knock-in mouse strain, containing a tamoxifen-inducible lineage specific Cre recombinase, to generate adult lung-specific mutations in Kras and Lkb1. We introduced a RosaYFP (lox-stop-lox-YFP) into the mutant background to specifically label and track lung epithelial cells during tumor progression and metastasis. This model (Kras G12D /Lkb1L/L/YFPL/-/Nkx2-1creER2+/- mice), will allow us to determine the timing of dissemination during the natural evolution of lung adenocarcinoma in vivo and correlate cell phenotype with the acquisition of invasive and tumor-initiating properties. We will test our hypothesize in year 2 (NCE) that (1) lung tumor cells invade and disseminate early in tumor evolution via EMT and (2) disseminated cancer cells exhibit a stem cell-like phenotype. Successful completion of this project promises to shift the current paradigm of lung cancer metastasis and will aid in early detection, and novel treatment approaches.