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A stress-induced early innate response causes multidrug tolerance in melanoma

Oncogene volume 34, pages 4448–4459 (2015)Cite this article

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A Corrigendum to this article was published on 26 January 2015

This article has been updated

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.

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Change history

  • 20 August 2015

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue.

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Acknowledgements

We would like to thank Marcus Absenger (ZMF, Medical University of Graz), Xin Xiao and Palmila Liu (The Wistar Institute, PA, USA) and Maria Grygar (Institute of Pathology, Medical University of Graz, Austria) for technical assistance. This work was supported by the PhD program ‘Molecular Medicine’ of the Medical University of Graz (to DRM and SD) and the Austrian Science foundation (FWF) projects SFB LIPOTOX F30 and W1226 DK ‘‘Metabolic and cardiovascular disease’’ (to GH). We thank Dr Atsushi Miyawaki, RIKEN, Wako-city, Japan, for providing the FUCCI constructs. The FUCCI work was supported by project grants APP1003637 (National Health and Medical Research Council) and RG 09-08 (Cancer Council New South Wales) to NKH.

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Authors and Affiliations

  1. Department of Dermatology, Cancer Biology Unit, Medical University of Graz, Graz, Austria

    D Ravindran Menon, E Bonyadi Rad & H Schaider

  2. Center for Medical Research, Medical University of Graz, Graz, Austria

    D Ravindran Menon, B Rinner, K Wagner, E Bonyadi Rad & H Schaider

  3. Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia

    D Ravindran Menon, H P Soyer & H Schaider

  4. Institute of Pathology, Medical University of Graz, Graz, Austria

    S Das, S Schauer, K Kashofer & G Hoefler

  5. The Wistar Institute, Philadelphia, PA, USA

    C Krepler, A Vultur, G Zhang, R Somasundaram & M Herlyn

  6. The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia

    N K Haass, H P Soyer, B Gabrielli & H Schaider

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  1. D Ravindran Menon
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  2. S Das
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  3. C Krepler
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  9. G Zhang
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  10. E Bonyadi Rad
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  11. N K Haass
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Correspondence to H Schaider.

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Supplementary Information accompanies this paper on the Oncogene website

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Ravindran Menon, D., Das, S., Krepler, C. et al. A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene 34, 4448–4459 (2015). https://doi.org/10.1038/onc.2014.372

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