SMAD signaling promotes melanoma metastasis independently of phenotype switching
| Autor: | Eylul Tuncer, Sandra N. Freiberger, Phil F. Cheng, Reinhard Dummer, Lukas Sommer, Daniel Zingg, Sandra Varum, Raquel R. Calçada, Mitchell P. Levesque, Ingo Kleiter, Chu-Xia Deng |
|---|---|
| Přispěvatelé: | University of Zurich, Sommer, Lukas |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
10017 Institute of Anatomy 610 Medicine & health 2700 General Medicine Disease SMAD Biology Disease-Free Survival Smad7 Protein Metastasis Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Humans Neoplasm Invasiveness Neoplasm Metastasis Melanoma Smad4 Protein Mice Knockout 10177 Dermatology Clinic General Medicine medicine.disease Phenotype In vitro Survival Rate 030104 developmental biology Tumor progression 030220 oncology & carcinogenesis Cancer research Signal Transduction Research Article Transforming growth factor |
| Zdroj: | Journal of Clinical Investigation. 129:2702-2716 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | The development of metastatic melanoma is thought to require the dynamic shifting of neoplastic cells between proliferative and invasive phenotypes. Contrary to this conventional "phenotype switching" model, we now show that disease progression can involve malignant melanoma cells simultaneously displaying proliferative and invasive properties. Using a genetic mouse model of melanoma in combination with in vitro analyses of melanoma cell lines, we found that conditional deletion of the downstream signaling molecule Smad4, which abrogates all canonical TGF-β signaling, indeed inhibits both tumor growth and metastasis. Conditional deletion of the inhibitory signaling factor Smad7, however, generated cells that are both highly invasive and proliferative, indicating that invasiveness is compatible with a high proliferation rate. In fact, conditional Smad7 deletion led to sustained melanoma growth and at the same time promoted massive metastasis formation, a result consistent with data indicating that low SMAD7 levels in patient tumors are associated with a poor survival. Our findings reveal that modulation of SMAD7 levels can overcome the need for phenotype switching during tumor progression and may thus represent a novel therapeutic target in metastatic disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|