During metastasis, carcinoma cells acquire the ability to invade extracellular matrix (ECM) to invade and intravasate. Although proteolytic activity is associated with increased metastasis and poor clinical outcome, the molecular triggers for matrix degradation in tumor cells are largely unknown. Our previous study demonstrated that the Twist1 transcription factor, a key regulator of early embryonic morphogenesis and a potent inducer of Epithelial-Mesenchymal Transition (EMT), plays an essential role in tumor metastasis. Our recent study found that a key role for Twist1 in metastasis is to promote matrix degradation and tumor invasion. Specifically, Twist1 induces the formation of invadopodia to perform local ECM degradation during tumor metastasis. Induction of invadopodia is essential for Twist1 to promote breast tumor metastasis in vivo and predicts poor survival in breast cancer patients. However, how Twist1 promotes invadopodia assembly and function are currently not well understood. Based on our preliminary data, we hypothesize that Twist1 induces the expression of an important membrane-associated protease that is essential for invadopodia-mediated ECM degradation and tumor metastasis. To test this hypothesis, our specific aims are as follows.
Aim1 :
We aim to determine whether induction of this protease is required for Twist1-induced invadopodia formation and function and understand how Twist1 regulates its expression.
Aim 2 :
We aim to determine how this protease regulates invadopodia assembly and function.
Aim 3 :
We aim to determine whether co-expression of Twist1 and this protease is associated with distant metastasis and poor survival in human breast tumors and to test the in vivo importance of this protease in promoting tumor progression and metastasis in a mouse tumor metastasis model.

Public Health Relevance

The proposed research aims to determine the regulation and function of a key protease in invadopodia- mediated matrix degradation and tumor metastasis. We believe that this work could uncover a novel regulatory machinery of tumor invasion and provide new targets for anti-metastasis therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA168689-02S1
Application #
8841517
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ogunbiyi, Peter
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2014-04-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2014
Total Cost
$20,153
Indirect Cost
$7,151
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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
Jung, Hae-Yun; Fattet, Laurent; Yang, Jing (2015) Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clin Cancer Res 21:962-968
Wei, Spencer C; Fattet, Laurent; Tsai, Jeff H et al. (2015) Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat Cell Biol 17:678-88
Chang, Andrew T; Liu, Yuanjie; Ayyanathan, Kasirajan et al. (2015) An evolutionarily conserved DNA architecture determines target specificity of the TWIST family bHLH transcription factors. Genes Dev 29:603-16

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