The majority of human cancers arise in the epithelial tissues of organs such as skin and colon. Uncontrolled proliferation of epithelial cells is often caused by aberrant signaling of growth factors and cytokines. A commonality among many epithelial tumors is an elevation of EGFR signaling. In fact, anti-EGFR strategies (EGFR monoclonal antibodies and small molecule tyrosine-kinase inhibitors;TKIs) are currently among the most common anti-cancer therapies. However, most anti-EGFR agents cause adverse side effects and are only partially effective due to quickly developed drug tolerance. We seek an alternative and novel strategy to treat EGFR-dependent carcinomas. Our proposal seeks to build on our recently made, and unexpected, discovery that TRPV3, a Ca2+ channel expressed in many epithelial tissues, including skin, colon, and prostate, is a key regulator of EGFR signaling. TRPV3 forms a signaling complex with TGF-a/EGFR;activation of EGFR leads to increased TRPV3 channel activity, which in turn stimulates TGF-a release mediated by ADAM-family sheddase. At the animal level, TRPV3-deficient mice exhibit similar hair/skin phenotypes as mice with defective TGF-a/EGFR signaling. Thus, TRPV3 could be a novel therapeutic target for skin and other epithelial cancers. Although ion channels are not known targets for cancer treatment, TRPV3 is recently reported to be a high-risk gene in colorectal cancer. Moreover, small molecule TRPV3 inhibitors are in clinical trials for reducing pain induced by inflammatory mediators, many of which are also potent tumor-promoting agents. Therefore, we specifically hypothesize that TRPV3 channel up-regulation in keratinocytes is a maladaption that accelerates skin tumorigenesis. Using animal models of skin carcinogenesis, we will investigate whether TRPV3 expression and channel function are up-regulated during epithelial malignancy, and whether genetic and pharmacological inactivation of TRPV3 may delay promotion/progression of epithelial tumors.
Our first aim i s to investigate TRPV3 expression/function during keratinocyte transformation and skin tumorigenesis.
Our second aim i s to study the roles of TRPV3 in the development of skin tumors using mice with genetically modified expression of TRPV3.
Our third aim i s to investigate the roles of TRPV3 in the development of skin tumors using TRPV3-specific small molecule inhibitors. Overall, the close interaction of TRPV3 and EGFR signaling on normal epidermis and the well-demonstrated role of EGFR signaling in cancer suggest a role of TRPV3 in epithelial tumorigenesis. The goal of this proposed research is to lay the groundwork necessary to develop new therapeutic strategies for skin and other epithelial cancers.

Public Health Relevance

The majority of human cancers arise in the epithelial tissues of organs such as breast, colon, prostate, and skin. The outcome of our proposed research should provide clinical insights into therapeutic approaches for skin and other epithelial cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR060837-02
Application #
8529459
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (05))
Program Officer
Baker, Carl
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$322,870
Indirect Cost
$109,120
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Xiaoli; Cheng, Xiping; Yu, Lu et al. (2016) MCOLN1 is a ROS sensor in lysosomes that regulates autophagy. Nat Commun 7:12109
Gu, Mingxue; Xu, Haoxing (2016) A painful TR(i)P to lysosomes. J Cell Biol 215:309-312
Li, Xinran; Rydzewski, Nicholas; Hider, Ahmad et al. (2016) A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation. Nat Cell Biol 18:404-17
Krishna, Shefali; Palm, Wilhelm; Lee, Yongchan et al. (2016) PIKfyve Regulates Vacuole Maturation and Nutrient Recovery following Engulfment. Dev Cell 38:536-47
Garrity, Abigail G; Wang, Wuyang; Collier, Crystal Md et al. (2016) The endoplasmic reticulum, not the pH gradient, drives calcium refilling of lysosomes. Elife 5:
(2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Miao, Yuxuan; Li, Guojie; Zhang, Xiaoli et al. (2015) A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion. Cell 161:1306-19
Cheng, Xiping; Zhang, Xiaoli; Yu, Lu et al. (2015) Calcium signaling in membrane repair. Semin Cell Dev Biol 45:24-31
Xu, Haoxing; Ren, Dejian (2015) Lysosomal physiology. Annu Rev Physiol 77:57-80
Wang, Wuyang; Gao, Qiong; Yang, Meimei et al. (2015) Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation. Proc Natl Acad Sci U S A 112:E1373-81

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