American Association for Cancer Research
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Supplementary Figures 1-3 from Metastatic Growth from Dormant Cells Induced by a Col-I–Enriched Fibrotic Environment

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posted on 2023-03-30, 19:40 authored by Dalit Barkan, Lara H. El Touny, Aleksandra M. Michalowski, Jane Ann Smith, Isabel Chu, Anne Sally Davis, Joshua D. Webster, Shelley Hoover, R. Mark Simpson, Jack Gauldie, Jeffrey E. Green
Supplementary Figures 1-3 from Metastatic Growth from Dormant Cells Induced by a Col-I–Enriched Fibrotic Environment

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ARTICLE ABSTRACT

Breast cancer that recurs as metastatic disease many years after primary tumor resection and adjuvant therapy seems to arise from tumor cells that disseminated early in the course of disease but did not develop into clinically apparent lesions. These long-term surviving, disseminated tumor cells maintain a state of dormancy, but may be triggered to proliferate through largely unknown factors. We now show that the induction of fibrosis, associated with deposition of type I collagen (Col-I) in the in vivo metastatic microenvironment, induces dormant D2.0R cells to form proliferative metastatic lesions through β1-integrin signaling. In vitro studies using a three-dimensional culture system modeling dormancy showed that Col-I induces quiescent D2.0R cells to proliferate through β1-integrin activation of SRC and focal adhesion kinase, leading to extracellular signal-regulated kinase (ERK)–dependent myosin light chain phosphorylation by myosin light chain kinase and actin stress fiber formation. Blocking β1-integrin, Src, ERK, or myosin light chain kinase by short hairpin RNA or pharmacologic approaches inhibited Col-I–induced activation of this signaling cascade, cytoskeletal reorganization, and proliferation. These findings show that fibrosis with Col-I enrichment at the metastatic site may be a critical determinant of cytoskeletal reorganization in dormant tumor cells, leading to their transition from dormancy to metastatic growth. Thus, inhibiting Col-I production, its interaction with β1-integrin, and downstream signaling of β1-integrin may be important strategies for preventing or treating recurrent metastatic disease. Cancer Res; 70(14); 5706–16. ©2010 AACR.