| Institution: | 1. Stem Cell Program, Boston Children's Hospital, Boston, MA, USA;2. Harvard Stem Cell Institute, Cambridge, MA, USA;3. Department of Genetics, Harvard Medical School, Boston, MA, USA;4. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA;5. Department of Medicine, University of Vermont, Burlington, VT, USA;6. Department of Medical Oncology, Dana‐Farber Cancer Institute, Boston, MA, USA;7. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA;8. Ludwig Center at Dana‐Farber, Harvard Cancer Center, MA, Boston, USA |
| Abstract: | 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. |
