Single-cell RNA sequencing reveals melanoma cell state-dependent heterogeneity of response to MAPK inhibitors.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-09-01 Epub Date: 2024-08-30 DOI:10.1016/j.ebiom.2024.105308

Su Yin Lim, Yingxin Lin, Jenny H Lee, Bernadette Pedersen, Ashleigh Stewart, Richard A Scolyer, Georgina V Long, Jean Y H Yang, Helen Rizos

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Abstract

Background: Melanoma is a heterogeneous cancer influenced by the plasticity of melanoma cells and their dynamic adaptations to microenvironmental cues. Melanoma cells transition between well-defined transcriptional cell states that impact treatment response and resistance.

Methods: In this study, we applied single-cell RNA sequencing to interrogate the molecular features of immunotherapy-naive and immunotherapy-resistant melanoma tumours in response to ex vivo BRAF/MEK inhibitor treatment.

Findings: We confirm the presence of four distinct melanoma cell states - melanocytic, transitory, neural-crest like and undifferentiated, and identify enrichment of neural crest-like and undifferentiated melanoma cells in immunotherapy-resistant tumours. Furthermore, we introduce an integrated computational approach to identify subsets of responding and nonresponding melanoma cells within the transcriptional cell states.

Interpretation: Nonresponding melanoma cells are identified in all transcriptional cell states and are predisposed to BRAF/MEK inhibitor resistance due to pro-inflammatory IL6 and TNFɑ signalling. Our study provides a framework to study treatment response within distinct melanoma cell states and indicate that tumour-intrinsic pro-inflammatory signalling contributes to BRAF/MEK inhibitor resistance.

Funding: This work was supported by Macquarie University, Melanoma Institute Australia, and the National Health and Medical Research Council of Australia (NHMRC; grant 2012860, 2028055).

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单细胞 RNA 测序揭示了黑色素瘤细胞对 MAPK 抑制剂反应的异质性。

背景：黑色素瘤是一种异质性癌症，受到黑色素瘤细胞的可塑性及其对微环境线索的动态适应性的影响。黑色素瘤细胞在定义明确的转录细胞状态之间转换，从而影响治疗反应和耐药性：在这项研究中，我们应用单细胞 RNA 测序技术，研究了免疫疗法无效黑色素瘤和免疫疗法耐药黑色素瘤对体内外 BRAF/MEK 抑制剂治疗的分子特征：我们证实了四种不同的黑色素瘤细胞状态--黑色素细胞、过渡性、神经嵴样和未分化，并确定了免疫治疗耐药肿瘤中神经嵴样和未分化黑色素瘤细胞的富集。此外，我们还介绍了一种综合计算方法，用于识别转录细胞状态中的应答和非应答黑色素瘤细胞亚群：无应答黑色素瘤细胞在所有转录细胞状态中都能被识别出来，由于IL6和TNFɑ信号的促炎作用，无应答黑色素瘤细胞容易对BRAF/MEK抑制剂产生耐药性。我们的研究为研究不同黑色素瘤细胞状态下的治疗反应提供了一个框架，并表明肿瘤内在的促炎信号导致了BRAF/MEK抑制剂的抗药性：本研究得到了麦考瑞大学、澳大利亚黑色素瘤研究所（Melanoma Institute Australia）和澳大利亚国家健康与医学研究委员会（NHMRC；Grant 2012860, 2028055）的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.