Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling

Ronald L. Chandler, Jeffrey S. Damrauer, Jesse R. Raab, Jonathan C. Schisler, Matthew D. Wilkerson, John P. Didion, Joshua Starmer, Daniel Serber, Della Yee, Jessie Xiong, David B. Darr, Fernando Pardo Manuel De Villena, William Y. Kim, Terry Magnuson

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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.

LanguageEnglish (US)
Article number6118
JournalNature Communications
Volume6
DOIs
StatePublished - Jan 1 2015

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mutations
Tumors
Carcinogenesis
cancer
Cytokines
Mutation
Carcinoma
tumors
cells
Phosphatidylinositol 3-Kinases
mice
Interleukin-6
Neoplasms
Cell growth
Phosphatidylinositols
Gene expression
penetrants
Chromatin
pathogenesis
chromatin

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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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 journalArticle

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. / Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. In: Nature Communications. 2015 ; Vol. 6.
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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.",
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