Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer.

Qinglei Gao,Taoran Zhang,Zongyuan Yang,Chaoyang Sun,Junbo Hu,Gang Chen,Li Meng,Jörg Wischhusen,Jianfeng Zhou,Yi Liu,Sen Xu,Xiaoting Li,Robert L Coleman,Víctor Manuel Vargas-Hernández,Thomas W Grunt,Xin Yang,Kenjiro Sawada,Bhavana Pothuri,Robert Fruscio,Xiang Zhou ,Xiao Wu ,Dan Liú ,Gong Chen ,Jin Park

doi:10.1084/jem.20180765

Abstract

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.

Highlights

High-grade serous ovarian cancer (HGSOC)—the most aggressive form of ovarian cancer (OC)—is characterized by insidious onset, rapid i.p. spread, and the development of massive ascites (Vaughan et al, 2011; Konecny et al, 2014; Nik et al, 2014)
HGSOC ascitic tumor cells (ATCs) display an aggressive nature To investigate the metastatic potential of ascites-derived tumor cells (ATCs), we isolated tumor epithelial cells from matched primary tumors, ascites, and solid metastases of HGSOC patients (Fig. 1 A)
To identify the cytokines secreted by activated fibroblasts that sustain ITGA5 expression in ATCs, we evaluated the cytokine profiles of conditioned medium (CM) from control Cancer-associated fibroblasts (CAFs) and from CAFs activated by ITGA5high SKOV3–derived CM or by transforming growth factor β (TGF-β1), which was introduced as an inducer or positive control of fibroblast activation

Summary

Introduction

High-grade serous ovarian cancer (HGSOC)—the most aggressive form of ovarian cancer (OC)—is characterized by insidious onset, rapid i.p. spread, and the development of massive ascites (Vaughan et al, 2011; Konecny et al, 2014; Nik et al, 2014). Its low-grade serous ovarian cancer (LGSOC) counterpart progresses slowly and has a more favorable outcome (Schmeler and Gershenson, 2008; Imamura et al, 2015). Their distinct molecular origins have been elucidated, the mechanisms mediating this discrepant biology relative to peritoneal spreading are poorly understood (Tung et al, 2009; Angarita et al, 2015). Considering the crucial role of peritoneal adhesion and the proposed function of spheroids during OC metastasis, we sought to investigate the processes by which ATCs assemble to form ascitic spheroids and subsequently execute peritoneal dissemination

Methods

Results

Conclusion