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To "grow" or "go": TMEM16A expression as a switch between tumor growth and metastasis in SCCHN

Shiwarski, Daniel and Shao , Chunbo and Bill, Anke and kim, jean and xiao, dong and bertrand, carol and seethala, raja and sano, daisuke and myers, jeffery and ha, patrick and grandis, jennifer and Gaither, Larry and puthenveedu, manojkumar and duvvuri, umamaheswar (2014) To "grow" or "go": TMEM16A expression as a switch between tumor growth and metastasis in SCCHN. Clinical cancer research : an official journal of the American Association for Cancer Research, 20 (17). pp. 4673-4688. ISSN 1078-0432

Abstract

PURPOSE: Tumor metastasis is the leading cause of death in patients with cancer. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis.

EXPERIMENTAL DESIGN: We evaluated 26 pairs of primary and metastatic lymph node (LN) tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. In addition, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis.

RESULTS: Compared with primary tumors, TMEM16A expression decreases in metastatic LNs of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial-to-mesenchymal transition (EMT) required the amino acid residue serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Furthermore, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT.

CONCLUSIONS: Together, our results identify TMEM16A, an eight transmembrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.

Item Type: Article
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:46
URI: https://oak.novartis.com/id/eprint/20980

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