Characterization of lung tumor-propagating cells reveals a role for CD24 and Yap/Taz in lung cancer progression and metastasis.

摘要

Lung cancer is the leading cause of cancer deaths worldwide. A large part of this high mortality rate is due to the onset of metastatic disease prior to diagnosis. Advances in treatment for metastatic disease may be achieved by understanding more about the identity of metastatic tumor cells and the mechanisms those cells employ to spread throughout the body. This thesis examined the relationship between cells capable of tumor propagation upon serial transplantation (tumor-propagating cells, or TPCs) and those with metastatic potential.;An orthotopic transplantation assay, in which tumor formation and metastatic growth were measured, revealed the relationship between lung TPCs and metastasis. First, CD24 was identified as a TPC marker in murine lung adenocarcinomas. CD24 expression status was not sufficient to identify lung cancer cells with enhanced metastatic capacity. Selection of tumors cells expressing both TPC markers Sca1 and CD24 enabled enrichment for TPCs with metastatic potential. Knockdown of CD24 in murine lung adenocarcinoma cells resulted in reduced migration in vitro and less metastatic tumor formation in vivo, demonstrating a functional role for CD24 in lung cancer cell metastasis.;Gene expression analysis demonstrated that many genes in the Hippo pathway and targets of the Hippo mediators Yap and Taz were differentially expressed in lung TPCs. A gene signature of Yap/Taz targets was significantly associated with worse lung adenocarcinoma patient survival and metastasis. Knockdown of Yap and Taz in murine lung adenocarcinoma cells showed that Yap and Taz are important for lung cancer cell migration. Taz was especially important for metastatic properties of these cells in vivo. Activation of Yap in a mouse model of lung adenocarcinoma increased tumor progression and number. These results show that Yap and Taz play an important role in lung tumor migration, progression and metastasis.;The work described here provides insight into the relationship between TPCs and metastasis and identifies pathways utilized by metastatic lung cancer cells. Future studies defining the detailed mechanisms by which CD24 and Yap/Taz activity affect lung cancer metastasis may lead to new treatment options for this deadly disease.