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 #
1R01CA168689-01
Application #
8342751
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$321,625
Indirect Cost
$114,125
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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Wu, Xuefeng; Zhang, Weizhou; Font-Burgada, Joan et al. (2014) Ubiquitin-conjugating enzyme Ubc13 controls breast cancer metastasis through a TAK1-p38 MAP kinase cascade. Proc Natl Acad Sci U S A 111:13870-5
Paz, H; Pathak, N; Yang, J (2014) Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene 33:4193-202
Tsai, Jeff H; Yang, Jing (2013) Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev 27:2192-206