Gopalan Vishaka, Wong Chun Wai, Leshem Rotem, Owen Luke, Vallius Tuulia, Shi Yingxiao, Jiang Yuhong, Pérez-Guijarro Eva, Wu Emily, Chin Sung, Ebersole Jessica, Smith Cari, Sassano Antonella, Constantino Maira Alves, Haley Michael J, Livak Ferenc, Simpson R Mark, Day Chi-Ping, Hurlstone Adam, Hannenhalli Sridhar, Merlino Glenn, Marie Kerrie L
Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT. United Kingdom.
bioRxiv. 2025 Jul 23:2022.10.14.512297. doi: 10.1101/2022.10.14.512297.
Melanoma plasticity, driven by phenotype state switching, underlies clinically relevant traits such as metastasis and therapy resistance. As melanoma progression is thought to recapitulate aspects of neural crest cell (NCC) development, understanding embryonic melanocyte specification and lineage fate decisions of closely related NCCs may illuminate the pathways co-opted during disease evolution. Here, we use a mouse model to isolate and sequence Dopachrome tautomerase (Dct) expressing NCCs, the precursors of melanocytes, at two key developmental stages. We classify these lineages and devise a Developmental Gene Module (DGM) scoring system to interrogate lineage state switching in melanoma samples. In bulk transcriptomes, activation of DGMs representing embryonic Schwann Cell Precursors (SCPs)-multipotent stem cells-in patient tumors predicts poor response to immune checkpoint inhibitors (ICI). Co-activation of SCP and Mesenchymal-like (Mes.) modules further correlates with resistance to MAPK inhibitors. Notably, single-cell analyses reveal that melanoma cells can simultaneously express multiple DGMs, forming "hybrid" states. Cells in a hybrid Neural/SCP state are enriched in early metastasis and ICI-resistant tumors and are insensitive to inflammatory stimuli. We demonstrate that targeting , a histone deacetylase associated with this Neural/SCP hybrid state, promotes a mesenchymal-like state switch, remodels the tumor microenvironment, and sensitizes melanoma cells to TNFα and tumors to ICI therapy. Our methodology thus reveals dynamic patterns of lineage state switching correlated with melanoma tumor evolution to drive insight into new therapeutic targets.
由表型状态转换驱动的黑色素瘤可塑性是转移和治疗抗性等临床相关特征的基础。由于黑色素瘤的进展被认为概括了神经嵴细胞（NCC）发育的各个方面，了解胚胎黑素细胞的特化以及密切相关的NCC的谱系命运决定可能会阐明疾病演变过程中共同采用的途径。在这里，我们使用小鼠模型在两个关键发育阶段分离并测序表达多巴色素互变异构酶（Dct）的NCC，即黑素细胞的前体。我们对这些谱系进行分类，并设计了一种发育基因模块（DGM）评分系统来研究黑色素瘤样本中的谱系状态转换。在批量转录组中，代表胚胎雪旺细胞前体（SCP）——多能干细胞——的DGM在患者肿瘤中的激活预示着对免疫检查点抑制剂（ICI）的反应不佳。SCP和间充质样（Mes.）模块的共同激活进一步与对MAPK抑制剂的抗性相关。值得注意的是，单细胞分析表明黑色素瘤细胞可以同时表达多个DGM，形成“混合”状态。处于神经/SCP混合状态的细胞在早期转移和ICI抗性肿瘤中富集，并且对炎症刺激不敏感。我们证明，靶向与这种神经/SCP混合状态相关的组蛋白脱乙酰酶，可促进间充质样状态转换，重塑肿瘤微环境，并使黑色素瘤细胞对TNFα敏感，使肿瘤对ICI治疗敏感。因此，我们的方法揭示了与黑色素瘤肿瘤演变相关的谱系状态转换的动态模式，以推动对新治疗靶点的深入了解。
