Breast tumors are often identified by manual palpation due to their apparent hardness compared to normal tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix stiffness can induce a malignant phenotype in cultured human mammary acini, suggesting that mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown. Our preliminary studies found that rigid matrix stiffness activates a key developmental program termed Epithelial- Mesenchymal Transition (EMT) to promote tumor metastasis. We therefore hypothesize that mechanical forces regulate EMT-inducing transcription factors through a novel mechanotransduction pathway to promote tumor invasion and metastasis. To test this hypothesis, we plan to 1-2) dissect the molecular mechanism by which mechanical forces activate EMT-inducing transcription factors; 3) determine the involvement of mechanoregulation of EMT-inducing transcription factors in promoting metastasis in vivo and in predicting long-term survival in human breast cancer patients.

Public Health Relevance

The proposed research aims to determine how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis. We believe that this work could uncover a novel regulatory machinery of tumor invasion and provide new targets for anti-metastasis therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Woodhouse, Elizabeth
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Choo, Sun; Wang, Ping; Newbury, Robert et al. (2018) Reactivation of TWIST1 contributes to Ewing sarcoma metastasis. Pediatr Blood Cancer 65:
Garcia, Daniel A; Baek, Christina; Estrada, M Valeria et al. (2018) USP11 Enhances TGF?-Induced Epithelial-Mesenchymal Plasticity and Human Breast Cancer Metastasis. Mol Cancer Res 16:1172-1184
Nakazawa, Youya; Taniyama, Yoshiaki; Sanada, Fumihiro et al. (2018) Periostin blockade overcomes chemoresistance via restricting the expansion of mesenchymal tumor subpopulations in breast cancer. Sci Rep 8:4013
Yeung, Kay T; Yang, Jing (2017) Epithelial-mesenchymal transition in tumor metastasis. Mol Oncol 11:28-39
Eckert, Mark A; Santiago-Medina, Miguel; Lwin, Thinzar M et al. (2017) ADAM12 induction by Twist1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions. J Cell Sci 130:2036-2048
Santiago-Medina, Miguel; Yang, Jing (2016) MENA Promotes Tumor-Intrinsic Metastasis through ECM Remodeling and Haptotaxis. Cancer Discov 6:474-6
Guo, Xing; Wang, Xiaorong; Wang, Zhiping et al. (2016) Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis. Nat Cell Biol 18:202-12
Majeski, Hannah E; Yang, Jing (2016) The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer. Mol Pharmacol 90:744-754
Banno, Asoka; Garcia, Daniel A; van Baarsel, Eric D et al. (2016) Downregulation of 26S proteasome catalytic activity promotes epithelial-mesenchymal transition. Oncotarget 7:21527-41
Wei, Spencer C; Yang, Jing (2016) Forcing through Tumor Metastasis: The Interplay between Tissue Rigidity and Epithelial-Mesenchymal Transition. Trends Cell Biol 26:111-120

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