Clinical outcomes for patients with ovarian and uterine cancers have not improved greatly in the past twenty years. To identify ovarian and uterine cancer vulnerabilities, we analyzed genome-scale CRISPR/Cas9 loss-of-function screens across 739 human cancer cell lines. We found that many ovarian cancer cell lines overexpress the phosphate importer SLC34A2, which renders them sensitive to loss of the phosphate exporter XPR1. We extensively validated the XPR1 vulnerability in cancer cell lines and found that the XPR1 dependency was retained in vivo. Overexpression of SLC34A2 is frequently observed in tumor samples and is regulated by PAX8 - a transcription factor required for ovarian cancer survival. XPR1 overexpression and copy number amplifications are also frequently observed. Mechanistically, SLC34A2 overexpression and impaired phosphate efflux leads to the accumulation of intracellular phosphate and cell death. We further show that proper localization and phosphate efflux by XPR1 requires a novel binding partner, KIDINS220. Loss of either XPR1 or KIDINS220 results in acidic vacuolar structures which precede cell death. These data point to the XPR1:KIDINS220 complex - and phosphate dysregulation more broadly - as a therapeutic vulnerability in ovarian cancer.

中文翻译：

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通过XPR1：KIDINS220蛋白复合物引起的磷酸失调是卵巢癌的治疗脆弱性

在过去的20年中，卵巢癌和子宫癌患者的临床结局并未得到很大改善。为了确定卵巢癌和子宫癌的脆弱性，我们分析了横跨739个人类癌细胞系的基因组规模的CRISPR / Cas9功能丧失筛选。我们发现许多卵巢癌细胞系过表达磷酸盐进口商SLC34A2，这使其对磷酸盐出口商XPR1的丢失很敏感。我们广泛验证了XPR1在癌细胞系中的脆弱性，并发现XPR1依赖性在体内得以保留。SLC34A2的过表达经常在肿瘤样品中观察到，并受PAX8调节-PAX8是卵巢癌生存所必需的转录因子。XPR1过表达和拷贝数扩增也经常被观察到。机械上，SLC34A2过表达和磷酸盐外排受损导致细胞内磷酸盐积累和细胞死亡。我们进一步表明XPR1的正确定位和磷酸盐外排需要新型的结合伴侣KIDINS220。XPR1或KIDINS220的丢失会导致细胞死亡之前的酸性液泡结构。这些数据指出XPR1：KIDINS220复合物-以及更广泛的磷酸盐失调-作为卵巢癌的治疗易感性。