Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity.

Yuko Matsumura,Satoru Shimizu,Atsushi Takano,Yoshihiro Mezawa,Michiaki Hamada,Harumi Saeki,Kazuyoshi Takeda,Yohei Miyagi,Toru Hiraga,Okio Hino,Kaoru Mogushi,Masayuki Ozawa,Yasuhisa Terao,Masaaki Abe,Tomoyuki Yokose,Hiromu Suzuki,Satoru Takeda,Ko Okumura,Kaidiliayi Sulidan,Nadila Wali,Yataro Daigo,Sonoko Habu,Akira Orimo,Yasuhiko Ito,Takahiko Itoh

doi:10.26508/lsa.201900425

Abstract

Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial-mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherinhiZEB1lo/neg: Ehi) state and another in a hybrid epithelial/mesenchymal (E-cadherinloZEB1hi: E/M) state. The Ehi cells highly express oncogenic cell-cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with Ehi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the Ehi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial-mesenchymal plasticity.

Highlights

The complete epithelial–mesenchymal transition (EMT) program, a main driver of the invasion-metastasis cascade, results in carcinoma cells losing all epithelial traits as well as cell–cell adhesion, instead acquiring mesenchymal properties (Thiery et al, 2009)
Tumor cell clusters invade and seed metastasis, but whether CAFinduced epithelial–mesenchymal plasticity contributes to this process remains unclear
carcinomaassociated fibroblasts (CAFs) induce collective cell invasion of cancer cell clusters and metastasis As CAFs have previously been demonstrated to prime collective invasion of tumor cell clusters (Gaggioli et al, 2007), we investigated their relevance to epithelial–mesenchymal plasticity

Summary

Introduction

The complete epithelial–mesenchymal transition (EMT) program, a main driver of the invasion-metastasis cascade, results in carcinoma cells losing all epithelial traits as well as cell–cell adhesion, instead acquiring mesenchymal properties (Thiery et al, 2009). Leader cells as evidenced by the mesenchymal trait are located at the front of the follower epithelial cancer clusters and drive their collective migration in response to environmental cues (Westcott et al, 2015; Mayor & EtienneManneville, 2016). Tumor cell clusters, designated “tumor budding” and “tumor emboli,” are assumed to intravasate by collective migration or passive shedding into the circulation in cancer patients (Grigore et al, 2016). Circulating tumor cell (CTC) clusters seed metastases significantly more often than single cancer cells in experimental murine models (Maddipati & Stanger, 2015; Cheung et al, 2016) and breast cancer patients (Aceto et al, 2014)

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