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.

In vitro long-term treatment with MAPK inhibitors induces melanoma cells with resistance plasticity to inhibitors while retaining sensitivity to CD8 T cells

“…However, Cheli et al described CD271 as an imperfect CSC marker since only the slow growing cells among the CD271 + subpopulation presented increased tumorigenic potential (40). Our results support those of Ravindran Menon et al (41), who demonstrated that PLX4032 increased CD271 expression in CM cells and induced the transition into a slow cycling state. The same phenotype was also observed when cells were exposed to different types of stress, such as hypoxia or nutrient starvation, and the authors proposed that these changes were part of an early innate response program.…”

Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state

“…The acquisition of transiently heritable states in drug‐treated melanoma cells is reminiscent of reversible drug tolerance previously shown to involve chromatin modifications sensitive to HDAC inhibition (Sharma et al , ; Ravindran Menon et al , ). We therefore performed a focused screen with a library of small‐molecule inhibitors of epigenome‐modifying enzymes to identify those that reduced NGFR induction by vemurafenib.…”

Notch4 Signaling Induces a Mesenchymal–Epithelial–like Transition in Melanoma Cells to Suppress Malignant Behaviors

“…qRT-PCR was performed as described previously (7) using gene-specific primers (Supplementary Table S3). The qPCR array (PAHS-090Z, Qiagen) was performed according to the manufacturer’s protocol using mRNA extracted from WM9.…”