Heterotypic CAF-tumor spheroids promote early peritoneal metastasis of ovarian cancer

作者：Qinglei Gao, Zongyuan Yang, Sen Xu, Xiaoting Li, Xin Yang, Ping Jin, Yi Liu, Xiaoshui Zhou, Taoran Zhang, Cheng Gong, Wei Xiao, Dan Liu, Chaoyang Sun, Gang Chen, Junbo Hu, Meng Li, Jianfeng Zhou, Kenjiro Sawada, Robert Fruscio, Thomas W. Grunt, Jörg Wischhusen, Víctor Manuel Vargas-Hernández, Bhavana Pothuri, Robert L. Coleman · 发表于：The Journal of Experimental Medicine · 年份：2019 · DOI：10.1084/jem.20180765 · 被引用次数：264 · 研究领域：Cancer Cells and Metastasis、Cancer Research and Treatments、Immune cells in cancer

High-grade serous ovarian cancer (HGSOC) is hallmarked by early onset of peritoneal dissemination, which distinguishes it from low-grade serous ovarian cancer (LGSOC). Here, we describe the aggressive nature of HGSOC ascitic tumor cells (ATCs) characterized by integrin α5high (ITGA5high) ATCs, which are prone to forming heterotypic spheroids with fibroblasts. We term these aggregates as metastatic units (MUs) in HGSOC for their advantageous metastatic capacity and active involvement in early peritoneal dissemination. Intriguingly, fibroblasts inside MUs support ATC survival and guide their peritoneal invasion before becoming essential components of the tumor stroma in newly formed metastases. Cancer-associated fibroblasts (CAFs) recruit ITGA5high ATCs to form MUs, which further sustain ATC ITGA5 expression by EGF secretion. Notably, LGSOC is largely devoid of CAFs and the resultant MUs, which might explain its metastatic delay. These findings identify a specialized MU architecture that amplifies the tumor–stroma interaction and promotes transcoelomic metastasis in HGSOC, providing the basis for stromal fibroblast-oriented interventions in hampering OC peritoneal propagation.