Abstract SP159: EMT

Abstract

During metastasis, epithelial tumor cells dissociate from each other, disseminate into the systemic circulation, and then establish secondary tumors in distant sites. A developmental program termed Epithelial-Mesenchymal Transition (EMT) is implicated in promoting the dissemination of single carcinoma cells during metastasis. Our recent studies aim to understand how EMT is dynamically regulated in response to signals from the tumor microenvironment and from the intracellular machineries to impact EMT and tumor metastasis. Specifically, I will present a mechanotransduction pathway that senses and transmits mechanincal cues from stiff matrix in the tumor microenvironment to promote EMT and invasion during tumor progression. Breast tumors are often detected due to their apparent “hardness” compared to normal tissues, and increasing matrix stiffness correlates with distant metastasis and poor survival in breast cancer patients. These observations raise the question of how mechanical forces generated by the rigid tumor ECM impact tumor progression and metastasis. In a hydrogel coupled with 3D Matrigel overlay culture system that recapitulates the range of physiological stiffness from normal mammary glands to breast tumors, increased ECM stiffness triggers Epithelial-Mesenchymal Transition (EMT), invasion and metastasis. We previously reported that the transcription factor Twist1 is an essential mechano-mediator that promotes EMT and metastasis in response to ECM stiffness. High matrix stiffness promotes Twist1 nuclear localization through phosphorylation-dependent regulation of its interaction with cytoplasmic anchor G3BP2. Using kinase screening and protein affinity purification, we identified a novel mechanoresponsive protein complex including an ephrin receptor and a Src-family kinase that promotes Twist1 phosphorylation and subsequent nuclear translocation in response to high matrix rigidity. Pharmacological and genetic inhibition of this mechanotransduction pathway blocks ECM stiffness-induced EMT and invasion in vitro and inhibits metastasis in human breast tumor xenografts. Our findings reveal a novel mechanotransduction pathway that responds to mechanical signals from the tumor microenvironment to drive EMT, invasion, and metastasis. Citation Format: J Yang. EMT [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP159.