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.
| Language | English (US) |
|---|---|
| Article number | 6118 |
| Journal | Nature Communications |
| Volume | 6 |
| DOIs | |
| State | Published - Jan 1 2015 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. / Chandler, Ronald L.; Damrauer, Jeffrey S.; Raab, Jesse R.; Schisler, Jonathan C.; Wilkerson, Matthew D.; Didion, John P.; Starmer, Joshua; Serber, Daniel; Yee, Della; Xiong, Jessie; Darr, David B.; De Villena, Fernando Pardo Manuel; Kim, William Y.; Magnuson, Terry.
In: Nature Communications, Vol. 6, 6118, 01.01.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
AU - Chandler,Ronald L.
AU - Damrauer,Jeffrey S.
AU - Raab,Jesse R.
AU - Schisler,Jonathan C.
AU - Wilkerson,Matthew D.
AU - Didion,John P.
AU - Starmer,Joshua
AU - Serber,Daniel
AU - Yee,Della
AU - Xiong,Jessie
AU - Darr,David B.
AU - De Villena,Fernando Pardo Manuel
AU - Kim,William Y.
AU - Magnuson,Terry
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84923102594&partnerID=8YFLogxK
U2 - 10.1038/ncomms7118
DO - 10.1038/ncomms7118
M3 - Article
VL - 6
JO - Nature Communications
T2 - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6118
ER -