文章：

一种肿瘤特异性分子网络通过强化Jun N末端激酶–Yorkie前馈环路促进果蝇肿瘤生长

A Tumor-Specific Molecular Network Promotes Tumor Growth inDrosophilaby Enforcing a Jun N-Terminal Kinase–Yorkie Feedforward Loop

原文发布日期：2 May 2024

DOI: 10.3390/cancers16091768

类型: Article

开放获取: 是

英文摘要：

Cancer cells expand rapidly in response to altered intercellular and signaling interactions to achieve the hallmarks of cancer. Impaired cell polarity combined with activated oncogenes is known to promote several hallmarks of cancer, e.g., activating invasion by increased activity of Jun N-terminal kinase (JNK) and sustained proliferative signaling by increased activity of Hippo effector Yorkie (Yki). Thus, JNK, Yki, and their downstream transcription factors have emerged as synergistic drivers of tumor growth through pro-tumor signaling and intercellular interactions like cell competition. However, little is known about the signals that converge onto JNK and Yki in tumor cells and enable tumor cells to achieve the hallmarks of cancer. Here, using mosaic models of cooperative oncogenesis (RasV12,scrib−) inDrosophila, we show thatRasV12,scrib−tumor cells grow through the activation of a previously unidentified network comprising Wingless (Wg), Dronc, JNK, and Yki. We show thatRasV12,scrib−cells show increased Wg, Dronc, JNK, and Yki signaling, and all these signals are required for the growth ofRasV12,scrib−tumors. We report that Wg and Dronc converge onto a JNK–Yki self-reinforcing positive feedback signal-amplification loop that promotes tumor growth. We found that the Wg–Dronc–Yki–JNK molecular network is specifically activated in polarity-impaired tumor cells and not in normal cells, in which apical-basal polarity remains intact. Our findings suggest that the identification of molecular networks may provide significant insights into the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis.

摘要翻译： 

癌细胞通过改变细胞间相互作用和信号传导通路，快速增殖以实现其恶性特征。已知细胞极性受损与癌基因激活共同促进多种癌症特征，例如通过增强Jun N末端激酶（JNK）活性激活侵袭能力，以及通过提高Hippo效应因子Yorkie（Yki）活性维持持续增殖信号。因此，JNK、Yki及其下游转录因子通过促肿瘤信号传导和细胞竞争等细胞间相互作用，已成为协同驱动肿瘤生长的关键因子。然而，关于肿瘤细胞中汇聚于JNK和Yki并使其实现癌症特征的信号通路，目前知之甚少。本研究利用果蝇协同致癌（RasV12,scrib−）嵌合模型，发现RasV12,scrib−肿瘤细胞通过激活一个由Wingless（Wg）、Dronc、JNK和Yki组成的新型信号网络实现生长。实验表明RasV12,scrib−细胞中Wg、Dronc、JNK和Yki信号传导均显著增强，且这些信号对RasV12,scrib−肿瘤生长均不可或缺。研究证实Wg与Dronc共同汇聚于JNK–Yki自我强化的正反馈信号放大环路，从而促进肿瘤生长。该Wg–Dronc–Yki–JNK分子网络特异性激活于极性受损的肿瘤细胞，而在顶端-基底极性保持完整的正常细胞中未被激活。本研究表明，分子网络的鉴定可为揭示促肿瘤发生过程中信号通路的关键生物学改变及矛盾信号提供重要见解。

原文链接：

A Tumor-Specific Molecular Network Promotes Tumor Growth inDrosophilaby Enforcing a Jun N-Terminal Kinase–Yorkie Feedforward Loop