title: A stress-induced early innate response causes multidrug tolerance in melanoma.
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.
authors.affiliation: Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.|Center for Medical Research, Medical University of Graz, Graz, Austria.|Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Ravindran Menon
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Das
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Krepler
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: A
authors.identifier: http://orcid.org/0000-0003-0068-9496
authors.initials: A
authors.lastname: Vultur
authors.affiliation: Center for Medical Research, Medical University of Graz, Graz, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Rinner
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Schauer
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: Center for Medical Research, Medical University of Graz, Graz, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Wagner
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.|Center for Medical Research, Medical University of Graz, Graz, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Bonyadi Rad
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: N K
authors.initials: NK
authors.lastname: Haass
authors.affiliation: Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: H P
authors.initials: HP
authors.lastname: Soyer
authors.affiliation: The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Gabrielli
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Somasundaram
authors.affiliation: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: The Wistar Institute, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria.|Center for Medical Research, Medical University of Graz, Graz, Austria.|Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.|The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Schaider
mesh_terms: D000818:Animals; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D011728:Pyridones / Q000627:therapeutic use; D011744:Pyrimidinones / Q000627:therapeutic use; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000502:physiology; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011728:Pyridones; D011744:Pyrimidinones; D017475:Receptors, Nerve Growth Factor; D012097:Repressor Proteins; C560077:trametinib; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human