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EMT cells increase breast cancer metastasis via paracrine GLI activation in
neighbouring tumour cells
#MMPMID28604738
Neelakantan D
; Zhou H
; Oliphant MUJ
; Zhang X
; Simon LM
; Henke DM
; Shaw CA
; Wu MF
; Hilsenbeck SG
; White LD
; Lewis MT
; Ford HL
Nat Commun
2017[Jun]; 8
(?): 15773
PMID28604738
show ga
Recent fate-mapping studies concluded that EMT is not required for metastasis of
carcinomas. Here we challenge this conclusion by showing that these studies
failed to account for possible crosstalk between EMT and non-EMT cells that
promotes dissemination of non-EMT cells. In breast cancer models, EMT cells
induce increased metastasis of weakly metastatic, non-EMT tumour cells in a
paracrine manner, in part by non-cell autonomous activation of the GLI
transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI
926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX
models. In human breast tumours, the EMT-transcription factors strongly correlate
with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings
indicate that EMT contributes to metastasis via non-cell autonomous effects that
activate the Hh pathway. Although all Hh inhibitors may act against tumours with
canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical
EMT-induced GLI activation.
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