Key Takeaways & Executive Findings
- •• TMEM16A knockdown significantly reduces melanoma cell migration, invasion, and adhesion in vitro, as shown by wound healing, transwell, and Matrigel assays. • Pharmacological inhibition of TMEM16A with T16inh-A01 and Caccinh-A01 mimics the effects of knockdown, confirming its role as a key mediator of metastatic processes. • TMEM16A promotes melanoma metastasis by upregulating mesenchymal markers (N-cadherin, Vimentin) and MMP9, which are critical for EMT and ECM remodeling. • In a pulmonary metastasis mouse model, TMEM16A knockdown completely prevented visible lung nodules, indicating that TMEM16A inhibition is a promising therapeutic strategy for suppressing melanoma metastasis.
Abstract
As a highly aggressive malignancy arising from melanocytes, malignant melanoma accounts for the majority of skin cancer-related deaths worldwide. Metastases, particularly lung and brain metastases, contribute significantly to mortality. Although targeted therapy (BRAF/MEK inhibitors) and immunotherapy (checkpoint inhibitors) have greatly improved the overall survival of patients, drug resistance and toxicity remain major clinical challenges. Therefore, exploring new approaches to combat melanoma metastasis is imperative. Melanoma metastasis involves multiple processes, including phenotype switching (epithelial-mesenchymal transition, EMT), migration, invasion and infiltration. Phenotype switching occurs at the early stage of metastasis and is characterized by the downregulation of epithelial markers (e.g., E-cadherin) and the upregulation of mesenchymal markers (e.g., N-cadherin and Vimentin). Metastasis depends on highly regulated and complex remodeling of the tumor microenvironment formed by cells as well as by biochemical and biophysical components of the extracellular matrix (ECM) and their intricate interactions within and around a solid tumor mass. These processes are primarily mediated by the altered expression of metastasis-associated genes, and targeting the expression of these genes may be a promising strategy for inhibiting melanoma metastasis. TMEM16A (also known as ANO1), a calcium-activated chloride channel (CaCC) localized to the plasma membrane and organelle membranes, is widely expressed in tissues such as airways, smooth muscles, and neurons, where it plays important physiological roles in regulating smooth muscle contraction and chloride ion secretion. Growing evidence indicates that TMEM16A is overexpressed in various cancers and contributes to tumor progression by increasing cell proliferation, invasion, and metastasis. The expression level of TMEM16A is closely related to tumor size and differentiation, is associated with advanced stage and poor prognosis, and can even be used as a biomarker for certain malignant tumors. We previously observed a high expression level of TMEM16A in a human melanoma cell line, A375, which harbors a BRAF V600E mutation, and demonstrated its role in promoting tumor growth. Here, we further showed that elevated TMEM16A expression contributes to melanoma metastasis.
1. Introduction
As a highly aggressive malignancy arising from melanocytes, malignant melanoma accounts for the majority of skin cancer-related deaths worldwide. Metastases, particularly lung and brain metastases, contribute significantly to mortality [1]. Although targeted therapy (BRAF/MEK inhibitors) and immunotherapy (checkpoint inhibitors) have greatly improved the overall survival of patients, drug resistance and toxicity remain major clinical challenges [2,3]. Therefore, exploring new approaches to combat melanoma metastasis is imperative.
Melanoma metastasis involves multiple processes, including phenotype switching (epithelial-mesenchymal transition, EMT), migration, invasion and infiltration [4]. Phenotype switching occurs at the early stage of metastasis and is characterized by the downregulation of epithelial markers (e.g., E-cadherin) and the upregulation of mesenchymal markers (e.g., N-cadherin and Vimentin). Metastasis depends on highly regulated and complex remodeling of the tumor microenvironment formed by cells as well as by biochemical and biophysical components of the extracellular matrix (ECM) and their intricate interactions within and around a solid tumor mass [5]. These processes are primarily mediated by the altered expression of metastasis-associated genes, and targeting the expression of these genes may be a promising strategy for inhibiting melanoma metastasis.
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Na Zhou, Chuangxin Pei, Xue Lu, Peng Shi, Siqi Wu, Huaqun Chen (2026). TMEM16A inhibition suppresses melanoma metastasis. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025133
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Frequently Asked Questions
What is TMEM16A and why is it important in melanoma?
TMEM16A (ANO1) is a calcium-activated chloride channel overexpressed in various cancers. In melanoma, it promotes tumor growth and metastasis by enhancing cell migration, invasion, and adhesion, making it a potential therapeutic target.
How does TMEM16A inhibition affect melanoma cell behavior?
Inhibition of TMEM16A, either by genetic knockdown or pharmacological inhibitors, significantly reduces melanoma cell migration, invasion, and adhesion to extracellular matrix components, as demonstrated in wound healing, transwell, and Matrigel assays.
What molecular mechanisms underlie TMEM16A's prometastatic effects?
TMEM16A promotes metastasis by upregulating mesenchymal markers such as N-cadherin and Vimentin, and matrix metalloproteinase 9 (MMP9), which facilitate epithelial-mesenchymal transition and extracellular matrix remodeling.
Does TMEM16A inhibition suppress melanoma metastasis in vivo?
Yes, in a pulmonary metastasis mouse model, TMEM16A knockdown completely prevented visible lung nodules, indicating that TMEM16A inhibition effectively suppresses melanoma metastasis in vivo.
What are the clinical implications of this study?
This study suggests that targeting TMEM16A could be a novel therapeutic strategy to prevent melanoma metastasis, potentially overcoming drug resistance and toxicity associated with current treatments.
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