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

Chandler RL, Damrauer JS, Raab JR, Schisler JC, Wilkerson MD, Didion JP, Starmer J, Serber D, Yee D, Xiong J, Darr DB, Pardo-Manuel de Villena F, Kim WY, Magnuson T - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R ovarian tumors and human OCCC share molecular characteristics(A) H&E stained image of Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R tumor histology. (B) Near-adjacent histological section showing HNF1β immunoreactivity by IHC. (A’,B’) High magnification images of regions demarcated by dashed boxes in A and B. (C) Box plots of normalized expression values of human OCCC discriminant genes (N=159) for all mouse tumor and human EOC subtype samples. Significant differences between the mouse tumors and each human histological EOC subtype were calculated using a Wilcoxon test (*significant p-value of <0.05; #not significant p-value=0.6). NS, not significant.
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Figure 5: Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R ovarian tumors and human OCCC share molecular characteristics(A) H&E stained image of Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R tumor histology. (B) Near-adjacent histological section showing HNF1β immunoreactivity by IHC. (A’,B’) High magnification images of regions demarcated by dashed boxes in A and B. (C) Box plots of normalized expression values of human OCCC discriminant genes (N=159) for all mouse tumor and human EOC subtype samples. Significant differences between the mouse tumors and each human histological EOC subtype were calculated using a Wilcoxon test (*significant p-value of <0.05; #not significant p-value=0.6). NS, not significant.

Mentions: In human OCCC, neoplastic cells that line luminal spaces often assume a ‘hobnail’ appearance, which crudely resembles a nucleus standing on the tip of a cytoplasmic stalk. Hobnail cells were often observed on the tumor periphery in regions where tumor cell exfoliation into luminal regions was occurring (Fig. 4D, I, K). Exfoliated, metastatic tumor cell aggregates often consisted of hobnail-shaped cells organized around either clear-cell or hyalinized cores (Fig. 4I). OSE hyperplasia and small clumps of hobnail cells were evident on the ovarian surface as early as one week following AdCRE injection, with exfoliated tumor cell aggregates and clear-cell-like features apparent at 2 weeks (Supplementary Fig. 3). The tumors were also positive for the human OCCC marker, HNF1β, by IHC (Fig. 5B). Thus, mouse ovarian tumors harboring coexistent ARID1A-PIK3CA mutations share histopathological features with human OCCC.


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

Chandler RL, Damrauer JS, Raab JR, Schisler JC, Wilkerson MD, Didion JP, Starmer J, Serber D, Yee D, Xiong J, Darr DB, Pardo-Manuel de Villena F, Kim WY, Magnuson T - Nat Commun (2015)

Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R ovarian tumors and human OCCC share molecular characteristics(A) H&E stained image of Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R tumor histology. (B) Near-adjacent histological section showing HNF1β immunoreactivity by IHC. (A’,B’) High magnification images of regions demarcated by dashed boxes in A and B. (C) Box plots of normalized expression values of human OCCC discriminant genes (N=159) for all mouse tumor and human EOC subtype samples. Significant differences between the mouse tumors and each human histological EOC subtype were calculated using a Wilcoxon test (*significant p-value of <0.05; #not significant p-value=0.6). NS, not significant.
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Related In: Results  -  Collection

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Figure 5: Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R ovarian tumors and human OCCC share molecular characteristics(A) H&E stained image of Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R tumor histology. (B) Near-adjacent histological section showing HNF1β immunoreactivity by IHC. (A’,B’) High magnification images of regions demarcated by dashed boxes in A and B. (C) Box plots of normalized expression values of human OCCC discriminant genes (N=159) for all mouse tumor and human EOC subtype samples. Significant differences between the mouse tumors and each human histological EOC subtype were calculated using a Wilcoxon test (*significant p-value of <0.05; #not significant p-value=0.6). NS, not significant.
Mentions: In human OCCC, neoplastic cells that line luminal spaces often assume a ‘hobnail’ appearance, which crudely resembles a nucleus standing on the tip of a cytoplasmic stalk. Hobnail cells were often observed on the tumor periphery in regions where tumor cell exfoliation into luminal regions was occurring (Fig. 4D, I, K). Exfoliated, metastatic tumor cell aggregates often consisted of hobnail-shaped cells organized around either clear-cell or hyalinized cores (Fig. 4I). OSE hyperplasia and small clumps of hobnail cells were evident on the ovarian surface as early as one week following AdCRE injection, with exfoliated tumor cell aggregates and clear-cell-like features apparent at 2 weeks (Supplementary Fig. 3). The tumors were also positive for the human OCCC marker, HNF1β, by IHC (Fig. 5B). Thus, mouse ovarian tumors harboring coexistent ARID1A-PIK3CA mutations share histopathological features with human OCCC.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.

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.

No MeSH data available.


Related in: MedlinePlus