RT Journal Article
SR Electronic
T1 Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 729491
DO 10.1101/729491
A1 Weirong Kang
A1 Yibo Fan
A1 Yinxiao Du
A1 Elina A. Tonkova
A1 Yi-Hsin Hsu
A1 Kel Vin Tan
A1 Stephanie Alexander
A1 Bin Sheng Wong
A1 Haocheng Yang
A1 Jingyuan Luo
A1 Kuo Yao
A1 Jiayao Yang
A1 Xin Hu
A1 Tingting Liu
A1 Yu Gan
A1 Jian Zhang
A1 Jean J. Zhao
A1 Konstantinos Konstantopoulos
A1 Peter Friedl
A1 Pek Lan Khong
A1 Aiping Lu
A1 Mien-Chie Hung
A1 Michael B. Brenner
A1 Jeffrey E. Segall
A1 Zhizhan Gu
YR 2019
UL http://biorxiv.org/content/early/2019/08/09/729491.abstract
AB Current prevailing knowledge on EMT (epithelial mesenchymal transition) deems epithelial cells acquire the characters of mesenchymal cells to be capable of invading and metastasizing on their own. One of the signature events of EMT is called “cadherin switch”, e.g. the epithelial E-cadherin switching to the mesenchymal Cadherin-11. Here, we report the critical events after EMT that cancer cells utilize cadherin-11 to hijack the endogenous cadherin-11 positive fibroblasts. Numerous 3-D cell invasion assays with high-content live cell imaging methods reveal that cadherin-11 positive cancer cells adhere to and migrate back and forth dynamically on the cell bodies of fibroblasts. By adhering to fibroblasts for co-invasion through 3-D matrices, cancer cells acquire higher invasion speed and velocity, as well as significantly elevated invasion persistence, which are exclusive characteristics of fibroblast invasion. Silencing cadherin-11 in cancer cells or in fibroblasts, or in both, significantly decouples such physical co-invasion. Additional bioinformatics studies and PDX (patient derived xenograft) studies link such cadherin-11 mediated cancer hijacking fibroblasts to the clinical cancer progression in human such as triple-negative breast cancer patients. Further animal studies confirm cadherin-11 mediates cancer hijacking fibroblasts in vivo and promotes significant solid tumor progression and distant metastasis. Moreover, overexpression of cadherin-11 strikingly protects 4T1-luc cells from implant rejection against firefly luciferase in immunocompetent mice. Overall, our findings report and characterize the critical post-EMT event of cancer hijacking fibroblasts in cancer progression and suggest cadherin-11 can be a therapeutic target for solid tumors with stroma. Our studies hence provide significant updates on the “EMT” theory that EMT cancer cells can hijack fibroblasts to achieve full mesenchymal behaviors in vivo for efficient homing, growth, metastasis and evasion of immune surveillance. Our studies also reveal that cadherin-11 is the key molecule that helps link cancer cells to stromal fibroblasts in the “Seed & Soil” theory.