PDF(Pubmed)
Abstract：
Tissue homeostasis via the elimination of aberrant cells is fundamental for organism survival. Cell competition is a key homeostatic mechanism, contributing to the recognition and elimination of aberrant cells, preventing their malignant progression and the development of tumors. Here, using Drosophila as a model organism, we have defined a role for protein tyrosine phosphatase 61F (PTP61F) (orthologue of mammalian PTP1B and TCPTP) in the initiation and progression of epithelial cancers. We demonstrate that a Ptp61F null mutation confers cells with a competitive advantage relative to neighbouring wild-type cells, while elevating PTP61F levels has the opposite effect. Furthermore, we show that knockdown of Ptp61F affects the survival of clones with impaired cell polarity, and that this occurs through regulation of the JAK-STAT signalling pathway. Importantly, PTP61F plays a robust non-cell-autonomous role in influencing the elimination of adjacent polarity-impaired mutant cells. Moreover, in a neoplastic RAS-driven polarity-impaired tumor model, we show that PTP61F levels determine the aggressiveness of tumors, with Ptp61F knockdown or overexpression, respectively, increasing or reducing tumor size. These effects correlate with the regulation of the RAS-MAPK and JAK-STAT signalling by PTP61F. Thus, PTP61F acts as a tumor suppressor that can function in an autonomous and non-cell-autonomous manner to ensure cellular fitness and attenuate tumorigenesis.
摘要：
通过消除异常细胞的组织稳态是生物体存活的基础。细胞竞争是一种关键的稳态机制，有助于识别和消除异常细胞，防止其恶性进展和肿瘤的发展。这里,使用果蝇作为模型生物，我们已经定义了蛋白酪氨酸磷酸酶61F(PTP61F)(哺乳动物PTP1B和TCPTP的直系同源物)在上皮癌的发生和发展中的作用.我们证明了Ptp61F无效突变赋予细胞相对于邻近的野生型细胞具有竞争优势。而提高PTP61F水平具有相反的效果。此外，我们发现敲低Ptp61F会影响细胞极性受损的克隆的存活，这是通过调节JAK-STAT信号通路而发生的。重要的是,PTP61F在影响相邻极性受损突变细胞的消除方面发挥强大的非细胞自主作用。此外，在肿瘤RAS驱动的极性受损肿瘤模型中，我们显示PTP61F水平决定了肿瘤的侵袭性，Ptp61F敲低或过表达，分别,增加或减少肿瘤大小。这些作用与PTP61F对RAS-MAPK和JAK-STAT信号的调节相关。因此，PTP61F充当肿瘤抑制因子,其可以以自主和非细胞自主方式起作用以确保细胞适合性并减弱肿瘤发生。
