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

Qinglei Gao, Zongyuan Yang, Sen Xu, Xiaoting Li, Xin Yang, Ping Jin, Yi Liu, Xiaoshui Zhou, Taoran Zhang, Cheng Gong, Xiao Wei, Dan Liu, Chaoyang Sun, Gang Chen, Junbo Hu, Li Meng, Jianfeng Zhou, Kenjiro Sawada, Robert Fruscio, Thomas W. GruntJörg Wischhusen, Víctor Manuel Vargas‑Hernández, Bhavana Pothuri, Robert L. Coleman

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)688-703
Number of pages16
JournalJournal of Experimental Medicine
Volume216
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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