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Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model
Published on: September 7, 2013
A stress-induced early innate response causes multidrug tolerance in melanoma
D Ravindran Menon1,2,3, S Das4, C Krepler5
1Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.
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.
Insights
Melanoma cells develop temporary drug resistance (induced drug-tolerant cells) in response to stress, which can revert. However, prolonged exposure leads to permanent resistance, highlighting the need to target these cells.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Acquired drug resistance is a significant obstacle in melanoma treatment.
- The mechanisms underlying the transition to permanent drug resistance remain unclear.
- Understanding early cellular responses is crucial for developing improved therapeutic strategies.
Purpose of the Study:
- To investigate the early cellular responses in melanoma cells upon drug exposure, hypoxia, or nutrient starvation.
- To characterize the properties of induced drug-tolerant cells (IDTCs) and their role in acquired drug resistance.
- To explore potential therapeutic targets for preventing or overcoming drug resistance in melanoma.
Main Methods:
- Induction of IDTCs in melanoma cells using drug exposure, hypoxia, or nutrient starvation.
- Analysis of cellular changes including chromatin remodeling, signaling pathways, and gene expression.
- Assessment of cell surface markers (CD271), differentiation markers (melan-A, tyrosinase), and aldehyde dehydrogenase (ALDH) activity.
- Evaluation of histone modifications (H3K4me3, H3K27me3, H3K9me3) and histone demethylase activity.
- Investigating the effect of drug holidays and gene knockdown (CD271, KDM5B) on IDTC transition and drug sensitivity.
Main Results:
- Drug exposure, hypoxia, or starvation induces an early innate response in melanoma cells, forming IDTCs with multidrug resistance.
- IDTCs exhibit characteristics of cancer stemness, increased angiogenic potential, and tumorigenicity, marked by elevated CD271 and ALDH activity, and loss of differentiation markers.
- IDTCs display altered histone methylation patterns (loss of H3K4me3/H3K27me3, gain of H3K9me3), indicating differential gene regulation.
- Drug holidays allow IDTCs to revert to drug-sensitive parental cells, while continuous drug exposure leads to irreversible resistance.
- Knockdown of CD271 or KDM5B partially inhibits the transition to IDTCs.
Conclusions:
- Induced drug-tolerant cells represent a crucial intermediate state in the development of acquired drug resistance in melanoma.
- Targeting IDTCs is essential for effective and sustainable melanoma management and preventing treatment failure.
- Further research into targeting IDTCs and associated pathways like CD271 and KDM5B is warranted.
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