Single-Cell Transcriptomics of Distinct Cell States in NRAS-Mutated Melanoma Transitioning to Drug Resistance: Elevated P2RX7 Levels Indicate Response to Targeted Therapy

Randic, Tijana; Magni, Stefano; Philippidou, Demetra; Grzyb, Kamil; Preis, Jasmin  Renate; Margue, Christiane; Nazarov, Petr V.; Mittelbronn, Michel; Frauenknecht, Katrin; Skupin, Alexander; Kreis, Stephanie

doi:10.2139/ssrn.4295386

Cited by 3 publications

(4 citation statements)

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“…Recently, P2X7 activation was associated with improved therapy responses in NRAS-mutant melanoma 85 , presumably by reducing the rise of resistant cells. This is contrary to the role of purinergic signaling in BRAF-mutant melanoma that enhances drug tolerance via ppERK reactivation during BRAFi therapy.…”

Section: Discussionmentioning

confidence: 99%

Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Stauffer,

Brinkley,

Jacobson

et al. 2023

Preprint

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SUMMARYWe report a previously unrecognized signaling mechanism underlying drug tolerance in BRAF-mutant melanoma treated with BRAF inhibitors. Its key feature is sustained intracellular Ca2+signaling initiated by purinergic ligand-gated cation channels, P2X receptors. Src family kinases act as mediators for cytoplasmic Ca2+spikes to activate ERK1/2, well-known to support cell survival and proliferation. An intriguing feature of this network is that extracellular ATP, virtually ubiquitous in living systems, is the ligand that can initiate Ca2+spikes via P2X channels. ATP is abundant in the tumor microenvironment and is released by dying cells, thereby implicating the death of drug-sensitive cells as a source of trophic stimuli that leads to ERK reactivation and drug tolerance. Such a mechanism immediately offers an explanation of the inevitable relapse after BRAFi treatment in BRAF-mutant melanoma.

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Section: Discussionmentioning

confidence: 99%

Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Stauffer,

Brinkley,

Jacobson

et al. 2023

Preprint

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“…Similarly, in NRAS-mutant melanoma cells treated with combination MEK and CDK4/6 inhibitors, scRNA-seq revealed distinct cell clusters reflecting heterogeneity in transcriptional response to treatment, and differences in response was postulated to cause outgrowth of intrinsically resistant melanoma subpopulations. 53 …”

Section: Next-generation Single-cell Rna Sequencing (Sc-rnaseq) In Me...mentioning

confidence: 99%

“…This study identified the ATP-gated ion channel P2RX7 as a potential target in delaying acquired resistance to CDK4/6 inhibitors. GSE230538 53 …”

Section: Next-generation Single-cell Rna Sequencing (Sc-rnaseq) In Me...mentioning

confidence: 99%

“… 52 Treatment of NRAS-mutant melanoma cells with MEK and CDK4/6 inhibitors induced two divergent drug responses: fast-adapting cells characterised by increased ion transmembrane transport and an immune-like state, and slow-adapting cells with features of senescence. 53 Hence, it is provocative to suggest that understanding the mechanisms of treatment response may provide novel approaches to circumvent melanoma cell adaptation and prevent the emergence of drug resistance.…”

Section: Next-generation Single-cell Rna Sequencing (Sc-rnaseq) In Me...mentioning

confidence: 99%

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Single-cell RNA sequencing in melanoma: what have we learned so far?

Lim,

Rizos

2024

eBioMedicine

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Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

Subhadarshini

Sahoo

Somarelli

et al. 2023

Preprint

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Phenotypic heterogeneity of melanoma cells contributes to drug tolerance, increased metastasis, and immune evasion in patients with progressive disease. Diverse mechanisms have been individually reported to shape extensive intra- and inter- tumoral phenotypic heterogeneity, such as IFN-gamma signaling and proliferative-invasive transition, but how their crosstalk impacts tumor progression remains largely elusive. Here, using dynamical systems modeling and analysis of publicly available transcriptomic data at both bulk and single-cell levels, we demonstrate that the emergent dynamics of a regulatory network comprising MITF, SOX10, SOX9, JUN and ZEB1 can recapitulate experimental observations about the co-existence of diverse phenotypes (proliferative, neural crest-like, invasive) and reversible cell-state transitions among them. These phenotypes have varied levels of PD-L1, thus driving variability in immunosuppression. We elucidate how this heterogeneity in PD-L1 levels can be aggravated by combinatorial dynamics of these regulators with IFN-gamma signaling. Our model predictions are corroborated by analysis of PD-L1 levels in pre- and post-treatment scenarios both in vitro and in vivo. Our calibrated dynamical model offers a platform to test combinatorial therapies and provide rational avenues for clinical management of metastatic melanoma.

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Single-Cell Transcriptomics of Distinct Cell States in NRAS-Mutated Melanoma Transitioning to Drug Resistance: Elevated P2RX7 Levels Indicate Response to Targeted Therapy

Cited by 3 publications

References 0 publications

Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Single-cell RNA sequencing in melanoma: what have we learned so far?

Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

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Single-Cell Transcriptomics of Distinct Cell States in NRAS-Mutated Melanoma Transitioning to Drug Resistance: Elevated P2RX7 Levels Indicate Response to Targeted Therapy

Cited by 3 publications

References 0 publications

Purinergic Ca2+signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Purinergic Ca2+signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Single-cell RNA sequencing in melanoma: what have we learned so far?

Dynamical modelling of proliferative-invasive plasticity and IFNγ signaling in melanoma reveals mechanisms of PD-L1 expression heterogeneity

Contact Info

Product

Resources

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Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma

Purinergic Ca²⁺signaling as a novel mechanism of drug tolerance in BRAF mutant melanoma