TY - JOUR
T1 - Post-EMT: Cadherin-11 mediates cancer hijacking fibroblasts
AU - Kang, Weirong
AU - Fan, Yibo
AU - Du, Yinxiao
AU - Tonkova, Elina A.
AU - Hsu, Yi-Hsin
AU - Tan, Kel Vin
AU - Alexander, Stephanie
AU - Wong, Bin Sheng
AU - Yang, Haocheng
AU - LUO, Jingyuan
AU - Yao, Kuo
AU - Yang, Jiayao
AU - Hu, Xin
AU - Liu, Tingting
AU - Gan, Yu
AU - Zhang, Jian
AU - Zhao, Jean J.
AU - Konstantopoulos, Konstantinos
AU - Friedl, Peter
AU - Khong, Pek Lan
AU - Lu, Aiping
AU - Hung, Mien-Chie
AU - Brenner, Michael B.
AU - Segall, Jeffrey E.
AU - Gu, Zhizhan
N1 - Funding Information:
This work was supported by Hong Kong University Grants Committee/ Research Grants Council Grants ECS22103319 and GRF17210618 to Z.G.; Hong Kong Baptist University Grants Startup/38- 402-94, FRG2/17-18/039 and SGT2/18-19/018 to Z.G.; The National Institute of Health Grants P01CA100324 and R21NS087624 to J.E.S.; The National Institute of Health Grant P30CA013330 to the Analytical Imaging Facility of the Albert Einstein College of Medicine; Hong Kong University Grants Committee/Research Grant Council Grant CRFC7018-14E to The MicroPET-MRI Laboratory of The University of Hong Kong.
Publisher copyright:
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved.
PY - 2020/8/27
Y1 - 2020/8/27
N2 - 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.
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.
U2 - 10.1101/729491
DO - 10.1101/729491
M3 - Article
JO - bioRxiv
JF - bioRxiv
SN - 2692-8205
ER -
