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

Ravindran Menon, D., Das, S., Krepler, C., Vultur, A., Rinner, B., Schauer, S., Kashofer, K., Wagner, K., Zhang, G., Bonyadi Rad, E., Haass, N. K., Soyer, H. P., Gabrielli, B., Somasundaram, R., Hoefler, G., Herlyn, M. and Schaider, H. (2015) A stress-induced early innate response causes multidrug tolerance in melanoma. Oncogene, 34 34: 4448-4459. doi:10.1038/onc.2014.372

Author Ravindran Menon, D.
Das, S.
Krepler, C.
Vultur, A.
Rinner, B.
Schauer, S.
Kashofer, K.
Wagner, K.
Zhang, G.
Bonyadi Rad, E.
Haass, N. K.
Soyer, H. P.
Gabrielli, B.
Somasundaram, R.
Hoefler, G.
Herlyn, M.
Schaider, H.
Title A stress-induced early innate response causes multidrug tolerance in melanoma
Journal name Oncogene   Check publisher's open access policy
ISSN 1476-5594
Publication date 2015-08-20
Year available 2014
Sub-type Article (original research)
DOI 10.1038/onc.2014.372
Open Access Status Not Open Access
Volume 34
Issue 34
Start page 4448
End page 4459
Total pages 12
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2015
Language eng
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 24 November 2014. Corrigendum: http://dx.doi.org/10.1038/onc.2014.432

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 5 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 08 Dec 2014, 10:46:22 EST by Nikolas Haass on behalf of School of Medicine