Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 3, Pages 688-703Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20180765
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Funding
- National Science Foundation of China [81630060, 81472783, 81372801, 81572570, 81502250, 81572725, 81602284, 81772787]
- 973 Program of China [2015CB553903]
- National Science and Technology Major Sub-Project [2018ZX10301402-002]
- Technical Innovation Special Project of Hubei Province [2018ACA138]
- National Key Research & Development Program of China [2016YFC0902901]
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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 alpha 5(high) (ITGA5(high)) 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 ITGA5(high) 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.
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