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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 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.

SUBMITTER: Shiwarski DJ

PROVIDER: S-EPMC4160843 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Shiwarski Daniel J DJ Shao Chunbo C Bill Anke A Kim Jean J Xiao Dong D Bertrand Carol A CA Seethala Raja S RS Sano Daisuke D Myers Jeffery N JN Ha Patrick P Grandis Jennifer J Gaither L Alex LA Puthenveedu Manojkumar A MA Duvvuri Umamaheswar U

Clinical cancer research : an official journal of the American Association for Cancer Research 20140611 17

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 identifi ...[more]

PMID: 24919570

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Project description:Many sharks and other marine taxa use natal areas to maximize survival of young, meaning such areas are often attributed conservation value. The use of natal areas is often linked to predator avoidance or food resources. However, energetic constraints that may influence dispersal of young and their use of natal areas are poorly understood. We combined swim-tunnel respirometry, calorimetry, lipid class analysis and a bioenergetics model to investigate how energy demands influence dispersal of young in a globally distributed shark. The school shark (a.k.a. soupfin, tope), Galeorhinus galeus, is Critically Endangered due to overfishing and is one of many sharks that use protected natal areas in Australia. Energy storage in neonate pups was limited by small livers, low overall lipid content and low levels of energy storage lipids (e.g. triacylglycerols) relative to adults, with energy stores sufficient to sustain routine demands for 1.3-4 days (mean ± SD: 2.4 ± 0.8 days). High levels of growth-associated structural lipids (e.g. phospholipids) and high energetic cost of growth suggested large investment in growth during residency in natal areas. Rapid growth (~40% in length) between birth in summer and dispersal in late autumn-winter likely increased survival by reducing predation and improving foraging ability. Delaying dispersal may allow prioritization of growth and may also provide energy savings through improved swimming efficiency and cooler ambient temperatures (daily ration was predicted to fall by around a third in winter). Neonate school sharks are therefore ill-equipped for large-scale dispersal and neonates recorded in the northwest of their Australian distribution are likely born locally, not at known south-eastern pupping areas. This suggests the existence of previously unrecorded school shark pupping areas. Integrated bioenergetic approaches as applied here may help to understand dispersal from natal areas in other taxa, such as teleost fishes, elasmobranchs and invertebrates.

Dataset Information

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

Publications

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

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