Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression.
Metastatic disease is a primary cause of cancer-related death, and factors governing tumor cell metastasis have not been fully elucidated. Here, we address this question by using tumor cell lines derived from mice that develop metastatic lung adenocarcinoma owing to expression of mutant K-ras and p53. Despite having widespread somatic genetic alterations, the metastasis-prone tumor cells retained a marked plasticity. They transited reversibly between epithelial and mesenchymal states, forming highly polarized epithelial spheres in three-dimensional culture that underwent epithelial-to-mesenchymal transition (EMT) following treatment with transforming growth factor-beta or injection into syngeneic mice. This transition was entirely dependent on the microRNA (miR)-200 family, which decreased during EMT. Forced expression of miR-200 abrogated the capacity of these tumor cells to undergo EMT, invade, and metastasize, and conferred transcriptional features of metastasis-incompetent tumor cells. We conclude that tumor cell metastasis is regulated by miR-200 expression, which changes in response to contextual extracellular cues.
Gibbons
Don L
DL
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. jkurie@mdanderson.org
Lin
Wei
W
Creighton
Chad J
CJ
Rizvi
Zain H
ZH
Gregory
Philip A
PA
Goodall
Gregory J
GJ
Thilaganathan
Nishan
N
Du
Liqin
L
Zhang
Yiqun
Y
Pertsemlidis
Alexander
A
Kurie
Jonathan M
JM
D000230:Adenocarcinoma / Q000503:physiopathology; D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005110:Extracellular Space / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008175:Lung Neoplasms / Q000503:physiopathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D016212:Transforming Growth Factor beta