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 tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolongs mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A and PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
Highlights
Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates
We found that Arid1afl/fl;(Gt)Rosa26Pik3ca*H1047R ovarian surface epithelium (OSE) cell proliferation was suppressed by treatment with anti-IL-6-neutralizing antibodies following mutation induction with Adenovirus CRE (AdCRE), and that recombinant IL-6 enhances normal OSE cell proliferation and IL-6-STAT3 signalling, further suggesting that IL-6 is both necessary and sufficient for tumour cell growth (Fig. 7d–f)
Our data support a genetic epistasis model wherein ARID1A and PIK3CA mutations cooperate and ovarian cancer can arise only when these genes are co-mutated in the mouse OSE
Summary
Ovarian clear-cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. EOC consists of four major histologic tumour subtypes (serous, clear-cell, endometrioid or mucinous) and originates from the coelomic epithelium, which is the precursor to the ovarian surface epithelium (OSE) and Mullerian ductal epithelium[2]. In addition to the histologic feature, each EOC subtype can be further classified into two distinct groups based on the disease progression, metastatic potential and molecular signature, with low-grade serous, clear-cell, mucinous and endometrioid subtypes being classified as Type I tumours and the high-grade serous subtype as Type II tumours[6]. Recent genome-sequencing efforts support a strong genetic contribution to OCCC aetiology based on the discovery of high-frequency (up to 50%) ARID1A tumour mutations[17,18]. ARID1A is a subunit within the SWI/SNF chromatin remodelling complex that facilitates target substrate recognition; its role in OCCC tumour initiation and progression has, yet, to be fully elucidated[24]
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