Zhao Sihua, Guo Yifan, Kuang Xiaoyu, Li Xiaoqin, Wu Chenxi, Lin Peng, Xie Qi, Zhai Zongzhao, Kong Du, Ma Xianjue
College of Life Sciences, Zhejiang University, 310058, Hangzhou, China.
School of Life Sciences, Westlake University, 310024, Hangzhou, China.
EMBO J. 2025 Aug 22. doi: 10.1038/s44318-025-00547-5.
Tumor heterogeneity, a hallmark of cancer, frequently leads to treatment failure and relapse. However, the intricate communication between various cell types within the tumor microenvironment and their roles in tumor progression in vivo remain poorly understood. Here we establish a novel tumor heterogeneity model in the Drosophila larval eye disc epithelium and dissect the in vivo mechanisms by combining sophisticated genetics with single-cell RNA sequencing. We found that mutation of the tricellular junction protein M6 in cells surrounding RasV12 benign tumors promotes their malignant transformation. Mechanistically, early RasV12//M6-/- tumors secrete Pvf1, which activates the Pvr receptor on hemocytes, facilitating their recruitment to the tumor site. These tumor-associated hemocytes secrete the Spätzle (Spz) ligand to activate the Toll receptor within the RasV12 tumors. This enhanced activation of the Toll pathway synergizes with RasV12 to promote malignant transformation through the JNK-Hippo signaling cascade. In summary, our study elucidates the complex interplay between genetically distinct oncogenic cells and between tumors and hemocytes, highlighting how hemocytes exploit the ancient innate immune system to coordinate tumor heterogeneity and drive tumor progression.
肿瘤异质性是癌症的一个标志，常常导致治疗失败和复发。然而，肿瘤微环境中各种细胞类型之间复杂的相互作用及其在体内肿瘤进展中的作用仍知之甚少。在这里，我们在果蝇幼虫眼盘上皮中建立了一种新型肿瘤异质性模型，并通过将复杂的遗传学与单细胞RNA测序相结合来剖析体内机制。我们发现，RasV12良性肿瘤周围细胞中的三联细胞连接蛋白M6发生突变会促进其恶性转化。从机制上讲，早期RasV12//M6-/-肿瘤分泌Pvf1，其激活血细胞上的Pvr受体，促进血细胞募集到肿瘤部位。这些肿瘤相关血细胞分泌Spätzle（Spz）配体，以激活RasV12肿瘤内的Toll受体。Toll途径的这种增强激活与RasV12协同作用，通过JNK-河马信号级联促进恶性转化。总之，我们的研究阐明了基因上不同的致癌细胞之间以及肿瘤与血细胞之间的复杂相互作用，突出了血细胞如何利用古老的先天免疫系统来协调肿瘤异质性并驱动肿瘤进展。
