Targeting of Cancer Stem Cells and Their Microenvironment in Early-Stage Mutant K-ras Lung Cancer
Technical Report,15 Sep 2014,14 Sep 2016
University of Texas Southwestern Medical Dallas United States
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The overall goal of this proposal is to understand the role of the Hh pathway in the maintenance and proliferation of lung adenocarcinoma progenitor cells and to establish therapeutic strategies that target the stem cell and its microenvironment for early stage lung cancer. We have completed the analysis of DHH expression in lung cancer cell lines, complementing previous findings of SHH and IHH. Using anti-SHHIHH antibody 5E1 conjugated with AlexaFluor 647, we have successfully identified aNOTCH3 SHH cell population that has characteristics of stem-like features. We have also tested inhibition of paracrine Hhpathway using both murine embryonic fibroblasts and normal murine lung fibroblasts. Whereas tumor growth is dependent on paracrine Hh pathway of MEFS, they are much less dependent on paracrine Hh pathway of lung fibroblasts. Analysis of potential Hh pathway targets of these fibroblasts showed that fibroblasts respond differently in response to SHH. We have completed the generation of LSL-KrasG12D Trp53flflR26luc mouse strain to test for tumor growth and metastasis. We have also generated orthotopic mouse models of lung adenocarcinoma cells with H23-FLG that express high levels of SHH. We will use these models to further pursue studies for the prevention of cancer metastasis.
- Medicine and Medical Research