Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition
Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition
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DOI：
10.1073/pnas.1911310116
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发表时间：
2019-12-17
影响因子：
11.1
通讯作者：
Castrillon, Diego H.
中科院分区：
文献类型：
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作者：
Cuevas, Ileana C.;Sahoo, Subhransu S.;Castrillon, Diego H.
子宫癌肉瘤是子宫内膜癌的一种侵袭性变异，其特征是不寻常的组织学特征，包括离散的恶性上皮和间质成分（癌和肉瘤）。最近的研究已经证实了单克隆起源，并且全面的基因组表征已经鉴定出突变，例如Tp 53和Pten。然而，子宫癌肉瘤的生物学起源和驱动因素的特定组合仍然是个谜。在这里，我们通过定义的遗传模型系统探讨了肿瘤抑制因子Fbxw 7在子宫内膜癌中的作用。Fbxw 7和Pten的失活导致癌前病变（类上皮内瘤变）和分化良好的类腺癌的形成。令人惊讶的是，所有的腺癌最终发展成具有癌性和肉瘤性成分（包括异源分化）的永久性子宫癌，产生了这种癌症类型的可靠的基因工程模型。基因组分析表明，大多数肿瘤自发获得Trp 53突变，指出三联途径（p53，PI 3 K和Fbxw 7）是支撑子宫癌肉瘤的关键组合，Fbxw 7是这种神秘的子宫内膜癌类型的关键驱动因素。谱系追踪提供了正式的遗传学证据，即子宫癌肉瘤细胞起源于子宫内膜上皮细胞，随后经历了显著的上皮-间质转化，这是获得由Fbxw 7特异性驱动的高度侵袭性表型的基础。
Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial-mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.