Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis.
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.
Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
Allison N
AN
Lau
Stephen J
SJ
Curtis
Christine M
CM
Fillmore
Samuel P
SP
Rowbotham
Morvarid
M
Mohseni
Darcy E
DE
Wagner
Alexander M
AM
Beede
Daniel T
DT
Montoro
Kerstin W
KW
Sinkevicius
Zandra E
ZE
Walton
Juliana
J
Barrios
Daniel J
DJ
Weiss
Fernando D
FD
Camargo
Kwok-Kin
KK
Wong
Carla F
CF
Kim
D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002465:Cell Movement; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse