Title |
A stress-induced early innate response causes multidrug tolerance in melanoma
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Published in |
Oncogene, November 2014
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DOI | 10.1038/onc.2014.372 |
Pubmed ID | |
Authors |
D Ravindran Menon, S Das, C Krepler, A Vultur, B Rinner, S Schauer, K Kashofer, K Wagner, G Zhang, E Bonyadi Rad, N K Haass, H P Soyer, B Gabrielli, R Somasundaram, G Hoefler, M Herlyn, H Schaider |
Abstract |
Acquired drug resistance constitutes a major challenge for effective cancer therapies with melanoma being no exception. The dynamics leading to permanent resistance are poorly understood but are important to design better treatments. Here we show that drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multidrug resistance, termed induced drug-tolerant cells (IDTCs). Transition into the IDTC state seems to be an inherent stress reaction for survival toward unfavorable environmental conditions or drug exposure. The response comprises chromatin remodeling, activation of signaling cascades and markers implicated in cancer stemness with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced aldehyde dehydrogenase (ALDH) activity and upregulation of histone demethylases. Accordingly, IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3 suggesting activation and repression of differential genes. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. However, upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug-resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.Oncogene advance online publication, 24 November 2014; doi:10.1038/onc.2014.372. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Australia | 1 | 33% |
Unknown | 2 | 67% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 3 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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United States | 2 | 1% |
Denmark | 1 | <1% |
Germany | 1 | <1% |
Unknown | 131 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 39 | 29% |
Researcher | 23 | 17% |
Student > Master | 13 | 10% |
Student > Doctoral Student | 10 | 7% |
Student > Bachelor | 7 | 5% |
Other | 19 | 14% |
Unknown | 24 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 51 | 38% |
Agricultural and Biological Sciences | 25 | 19% |
Medicine and Dentistry | 13 | 10% |
Immunology and Microbiology | 4 | 3% |
Social Sciences | 3 | 2% |
Other | 14 | 10% |
Unknown | 25 | 19% |