To “Grow” or “Go”: TMEM16A Expression as a Switch between Tumor Growth and Metastasis in SCCHN

Abstract

Purpose Tumor metastasis is the leading cause of death in cancer patients. 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 tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. Additionally, 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 to primary tumors, TMEM16A expression decreases in metastatic lymph nodes 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. Further, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT. Conclusions Together, our results identify TMEM16A, an eight trans-membrane 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.

Role of volume-regulated and calcium-activated anion channels in cell volume homeostasis, cancer and drug resistance

“…A pro-proliferative role of ANO1 is found in most cancer cells investigated 118,[141][142][143][144][145][146] and Stanich and coworkers demonstrated that ANO1 regulates cell proliferation at the G1/S transition in the cell cycle. 147 Other studies, however, show that cell proliferation in certain cell types is unaffected by ANO1, e.g.…”

“…139 In contrast, Shiwarshi and coworkers find that reduced ANO1 expression slows proliferation and allow metastatic progression and they suggest that ANO1 expression is a switch between growth and metastasis. 143 …”

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma

“…(Britschgi et al, 2013;Bill et al, 2015), but may also directly engage with MAP kinase pathways to promote growth and survival (Duvvuri et al, 2012;Sui et al, 2014). Although it is often reported in association with metastasis and recurrence in translational studies, other studies have reported effects on proliferation and local invasion (Ruiz et al, 2012;Shiwarski et al, 2014;Jia et al, 2015), suggesting the tumourigenic functions of Ano1 may be more complex than a 'grow to go' switch.…”

Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells

“…As would be predicted based on these results, reduced levels of CFTR are associated with poor prognosis in breast cancer patients (Zhang et al 2013a). More recent studies have begun to explore chloride channels in the context of EMT in other cancer types, such as squamous cell carcinomas of the head and neck (Shiwarski et al 2014). TMEM16A (also known as ANO1), is one of a reported subset (termed Anoctamins) of calcium activated chloride channels (Kunzelmann et al 2011).…”

“…MCF-7). Indeed, expression of the EMT Shiwarski et al (2014) transcription factor Snail supresses CLCA2 protein in the human breast cell line MCF10A, and CLCA2 levels are reduced in subpopulations of cells from the human mammary epithelial (HMLE) cell line that are enriched in mesenchymal markers (Walia et al 2012). Moreover, CLCA2 levels are reduced during EMT induced by TGFβ (Yu et al 2013).…”