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Data from SPIN90 Depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression

Posted on 2023-03-31 - 00:42
Abstract

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710–22. ©2017 AACR.

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FUNDING

National Research Foundation of Korea

Bio Imaging and Cell Logistics Research Center

Brain Research Program

Mid-Career Research Program

Basic Science Research Program

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Cancer Research

AUTHORS (15)

  • Eunae You
    Yun Hyun Huh
    Ahreum Kwon
    So Hee Kim
    In Hee Chae
    Ok-Jun Lee
    Je-Hwang Ryu
    Min Ho Park
    Ga-Eon Kim
    Ji Shin Lee
    Kun Ho Lee
    Yong-Seok Lee
    Jung-Woong Kim
    Sangmyung Rhee
    Woo Keun Song
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