|
|
|
|
|
|
|
|
abstract
Ovarian
clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer
with high ARID1A mutation rates. Here we present a mutant mouse model of
OCCC. We find that ARID1A inactivation is not sufficient for tumour
formation, but requires concurrent activation of the phosphoinositide
3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly
penetrant tumours with OCCC-like histopathology, culminating in
haemorrhagic ascites and a median survival period of 7.5 weeks.
Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs
mouse survival by inhibiting the tumour cell growth. Cross-species gene
expression comparisons support a role for IL-6 inflammatory cytokine
signalling in OCCC pathogenesis. We further show that ARID1A and PIK3CA
mutations cooperate to promote tumour growth through sustained IL-6
overproduction. Our findings establish an epistatic relationship between
SWI/SNF chromatin remodelling and PI3K pathway mutations in OCCC and
demonstrate that these pathways converge on pro-tumorigenic cytokine
signalling. We propose that ARID1A protects against inflammation-driven
tumorigenesis.
0 comments :
Post a Comment
Your comments?
Note: Only a member of this blog may post a comment.