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Lau, Allison N; Curtis, Stephen J; Fillmore, Christine M; Rowbotham, Samuel P; Mohseni, Morvarid; Wagner, Darcy E; Beede, Alexander M; Montoro, Daniel T; Sinkevicius, Kerstin W; Walton, Zandra E; Barrios, Juliana; Weiss, Daniel J; Camargo, Fernando D; Wong, Kwok-Kin; Kim, Carla F
EMBO journal, 3 March 2014, Letnik: 33, Številka: 5Journal Article
Metastasis is the leading cause of morbidity for lung cancer patients. Here we demonstrate that murine tumor propagating cells (TPCs) with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. CD24 knockdown decreased the metastatic potential of lung cancer cell lines resembling TPCs. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. The TPC signature was enriched for genes in the Hippo signaling pathway. Knockdown of the Hippo mediators Yap1 or Taz decreased in vitro cellular migration and transplantation of metastatic disease. Furthermore, constitutively active Yap was sufficient to drive lung tumor progression in vivo. These results demonstrate functional roles for two different pathways, CD24‐dependent and Yap/Taz‐dependent pathways, in lung tumor propagation and metastasis. This study demonstrates the utility of TPCs for identifying molecules contributing to metastatic lung cancer, potentially enabling the therapeutic targeting of this devastating disease. Synopsis The molecular characterization of tumor‐propagating cells in mouse models of lung cancer reveals CD24+/Sca1+ and increased Yap/Taz activity as predictive for tumor metastasis. Murine lung TPCs with the markers Sca1 and CD24 are enriched for metastatic potential in orthotopic transplantation assays. In lung cancer patient data sets, metastatic spread and patient survival could be stratified with a murine lung TPC gene signature. Knockdown of the Hippo mediators Yap1 or Taz decreased migration and metastatic potential of lung cancer cells. Yap activation was sufficient for driving tumor progression in the Kras mouse model of lung cancer. The molecular characterization of tumor‐propagating cells in mouse models of lung cancer reveals CD24+/Sca1+ and increased Yap/Taz activity as predictive for tumor metastasis.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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