Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A-Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell-lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal (EM) plasticity phenotype, and elevated secretion of the tumorigenic cytokine IGFBP2. Therapeutic targeting of the IGFBP2/IGF1R signaling axis using small molecules and genetic approaches resulted in marked tumor growth inhibition. Mechanistically, PP2A regulated IGFBP2 expression through the transcription factor, NF-κB, which harbors a B56 recognition motif. Collectively, these results identify a role for PP2A in regulating paracrine cancer cell signaling that can be targeted to block the initiation and metastasis of high-grade uterine cancer.

中文翻译：

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突变型 PP2A 诱导 IGFBP2 分泌促进高级别子宫癌的发展


子宫浆液性癌 （USC） 和子宫癌肉瘤 （UCS） 肿瘤具有独特的侵袭性，表明原发肿瘤本质上具有播散和转移的能力。以前的工作确定了 PPP2R1A 内的突变热点，它编码蛋白质磷酸酶 2A （PP2A） 的 Aα 支架亚基，PP2A 是一种异源三聚体丝氨酸/苏氨酸磷酸酶。两种复发性杂合PPP2R1A突变 P179R 和 S256F 仅发生在子宫癌的高级别亚型中，可驱动肿瘤发生和转移。阐明 PP2A-Aα 突变体促进肿瘤发展和进展的机制可能有助于确定治疗机会。在这里，我们表明这些突变体在 USC/UCS 细胞系中的表达增强了肿瘤起始能力，驱动了杂交上皮-间充质 （EM） 可塑性表型，并提高了致瘤细胞因子 IGFBP2 的分泌。使用小分子和遗传方法对 IGFBP2/IGF1R 信号轴进行治疗靶向，导致显着的肿瘤生长抑制。从机制上讲，PP2A 通过转录因子 NF-κB 调节 IGFBP2 表达，NF-κB 含有 B56 识别基序。总的来说，这些结果确定了 PP2A 在调节旁分泌癌细胞信号传导中的作用，该信号传导可以靶向阻断高级别子宫癌的发生和转移。