Persister state-directed transitioning and vulnerability in melanoma

Abstract

Melanoma is a highly plastic tumor characterized by dynamic interconversion of different cell identities depending on the biological context. Melanoma cells with high expression of the H3K4 demethylase KDM5B (JARID1B) rest in a slow-cycling, yet reversible persister state. Over time, KDM5Bhigh cells can promote rapid tumor repopulation with equilibrated KDM5B expression heterogeneity. The cellular identity of KDM5Bhigh persister cells has not been studied so far, missing an important cell state-directed treatment opportunity in melanoma. Here, we have established a doxycycline-titratable system for genetic induction of permanent intratumor expression of KDM5B and screened for chemical agents that phenocopy this effect. Transcriptional profiling and cell functional assays confirmed that the dihydropyridine 2-phenoxyethyl 4-(2-fluorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylate (termed Cpd1) supports high KDM5B expression and directs melanoma cells towards differentiation along the melanocytic lineage and to cell cycle-arrest. The high KDM5B state additionally prevents cell proliferation through negative regulation of cytokinetic abscission. Moreover, treatment with Cpd1 promoted the expression of the melanocyte-specific tyrosinase gene specifically sensitizing melanoma cells for the tyrosinase-processed antifolate prodrug 3-O-(3,4,5-trimethoxybenzoyl)-(–)-epicatechin (TMECG). In summary, our study provides proof-of-concept for a dual hit strategy in melanoma, in which persister state-directed transitioning limits tumor plasticity and primes melanoma cells towards lineage-specific elimination.

Engaging plasticity: Differentiation therapy in solid tumors

“…Additionally, an acquisition of mesenchymal identity in HER2-amplified breast cancer cells upon treatment with Lapatinib was demonstrated ( Hangauer et al, 2017 ). Following these discoveries, efforts were made to detect and target the vulnerabilities of drug-tolerant cells, in various cancers and treatments ( Hangauer et al, 2017 ; Chauvistré et al, 2022 ). A recently published work identified a unique sub-population of cycling persister cells that can potentially be targeted therapeutically ( Oren et al, 2021 ).…”

Cellular Invasion Assay for the Real-Time Tracking of Individual Cells in Spheroid or Tumor-like Mimics

“…Figure b plots the persister cells, which moved throughout the entire 48 h experiment. The persister cell framework is new in cancer biology, adapted from a well-established concept in microbiology. , In this framework, drug-resistant cells in tumors are no longer attributed to metabolic arrest or quiescence but rather persister cells with an innate or adopted aggressive phenotype . The decrease in the number of cells tracked between the all and persister categories is due to arrested movement, loss of signal, or cells moving outside the imaging region.…”

“…49,50 In this framework, drug-resistant cells in tumors are no longer attributed to metabolic arrest or quiescence but rather persister cells with an innate or adopted aggressive phenotype. 51 The decrease in the number of cells tracked between the all and persister categories is due to arrested movement, loss of signal, or cells moving outside the imaging region. Both plots show cells invaded a range of distances, with the average cell movement decreasing as distance from the source of oxygen and nutrients increases.…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…These KDM5B high subpopulations also contribute to intrinsic multidrug resistance by promoting oxidative phosphorylation and maintaining a high ratio of reduced-to-oxidized glutathione [103,104]. On the other hand, enforced KDM5B expression limits tumor plasticity and heterogeneity, resulting in the elimination of melanoma cells by promoting melanocytic differentiation [105]. The authors of a recent study identified an immune evasion function driven by KDM5B in melanoma [44].…”