TY - JOUR
T1 - Heterotypic CAF-tumor spheroids promote early peritoneal metastatis of ovarian cancer
AU - Gao, Qinglei
AU - Yang, Zongyuan
AU - Xu, Sen
AU - Li, Xiaoting
AU - Yang, Xin
AU - Jin, Ping
AU - Liu, Yi
AU - Zhou, Xiaoshui
AU - Zhang, Taoran
AU - Gong, Cheng
AU - Wei, Xiao
AU - Liu, Dan
AU - Sun, Chaoyang
AU - Chen, Gang
AU - Hu, Junbo
AU - Meng, Li
AU - Zhou, Jianfeng
AU - Sawada, Kenjiro
AU - Fruscio, Robert
AU - Grunt, Thomas W.
AU - Wischhusen, Jörg
AU - Vargas‑Hernández, Víctor Manuel
AU - Pothuri, Bhavana
AU - Coleman, Robert L.
N1 - Publisher Copyright:
© 2019 Gao et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
PY - 2019/3/1
Y1 - 2019/3/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20180765
DO - 10.1084/jem.20180765
M3 - Article
C2 - 30710055
AN - SCOPUS:85062407714
SN - 0022-1007
VL - 216
SP - 688
EP - 703
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -