KAI1/CD82 is a metastasis suppressor of solid tumors. The mechanism of KAI1/CD82- mediated metastasis suppression still remains largely elusive. Recent studies indicate that KAI1/CD82 induces the reorganization of membrane microdomains such as lipid rafts and tetraspanin-enriched microdomain (TEM), attenuates growth factor and integrin signaling, and inhibits cell protrusion and retraction. Notably, we also found that KAI1/CD82 suppresses cancer metastasis by inhibiting cancer cell invasiveness. Thus, how KAI1/CD82 inhibits cancer cell movement becomes the outstanding question to understand how KAI1/CD82 suppresses cancer metastasis. We hypothesize that KAI1/CD82 inhibits cancer cell migration and invasion through re-organizing membrane microdomains and consequently reducing protrusive and retraction processes and the outside-in mitogenic signaling. To elucidate how KAI1 suppresses cancer invasion and metastasis, we will first carry out the structural and functional characterization of KAI1/CD82-containing TEM by i) identifying the structural element(s) in CD82 molecule that physically links TEM to lipid rafts, ii) systematically characterizing the protein and lipid components of CD82-positive TEM, and iii) analyze the trafficking and subcellular localization of CD82- containing TEM. Secondly, we will determine the mechanism by which KAI1/CD82-containing TEM regulates the cellular motile activities by addressing how CD82-containing TEM renders membrane curvature and trafficking. We will also assess the roles of CD82-induced alterations in membrane curvature and trafficking in i) membrane motile activities, ii) mitogenic signaling, and iii) CD82-mediated suppression of cancer invasion. Finally, we will determine the mechanism by which KAI1/CD82 inhibits cancer invasion in vivo by addressing i) through which cellular motile activity CD82 suppresses cancer invasion in vivo, ii) the contributions of the proteins physically or functionally associated with CD82 to CD82-mediated suppression of cancer invasion;and iii) whether the CD82 features analyzed above are crucial for its suppression of cancer invasion in vivo. Together, the proposed study will enable us to i) understand how KAI1/CD82 regulates cell migration, cancer invasion, and cancer metastasis as an organizer for membrane microdomains and ii) unveil a novel mechanisms by which cell motility and cancer metastasis are regulated, i.e., membrane curvature and trafficking regulates invasion and metastasis. From the in-depth in vitro and in vivo mechanistic study of KAI1/CD82, we will develop an integrated understanding of cancer invasion and metastasis, which will ultimately lead to the development of KAI1/CD82 into a diagnostic marker and therapeutic target for cancer invasion and metastasis.

Public Health Relevance

Because cancer metastasis is the major cause of the death of cancer patients, understanding how cancer becomes metastatic is crucial for the cancer treatment. In this project, we propose to determine how metastasis suppressor KAI1/CD82 inhibits cancer cell invasion and metastasis at molecular and cellular levels and our proposed studies will provide insight into the general mechanism of cancer metastasis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA096991-10S1
Application #
8792665
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Lin, Alison J
Project Start
2002-08-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
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Li, Xin; Zhang, Xin A; Li, Xiaoqing et al. (2015) MYC-mediated synthetic lethality for treating tumors. Curr Cancer Drug Targets 15:99-115
Feng, Jin; Huang, Chao; Wren, Jonathan D et al. (2015) Tetraspanin CD82: a suppressor of solid tumors and a modulator of membrane heterogeneity. Cancer Metastasis Rev 34:619-33
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Liu, Wei M; Zhang, Feng; Moshiach, Simon et al. (2012) Tetraspanin CD82 inhibits protrusion and retraction in cell movement by attenuating the plasma membrane-dependent actin organization. PLoS One 7:e51797
Guo, Qiusha; Xia, Bing; Zhang, Feng et al. (2012) Tetraspanin CO-029 inhibits colorectal cancer cell movement by deregulating cell-matrix and cell-cell adhesions. PLoS One 7:e38464
Zhang, Xin A; Huang, Chao (2012) Tetraspanins and cell membrane tubular structures. Cell Mol Life Sci 69:2843-52

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