美国纪念斯隆-凯特琳癌症中心Richard M. White小组揭示了机械约束控制黑色素瘤的表型可塑性。相关论文于2025年8月27日发表于国际顶尖学术期刊《自然》杂志上。

在这里，该课题组人员证明了机械约束通过染色质重塑介导表型转换。使用斑马鱼黑色素瘤模型和人类样本，该课题组在肿瘤和周围微环境之间的界面上分析了肿瘤细胞。界面细胞的形态分析显示细胞核呈椭圆形，暗示受到邻近组织的机械约束。空间和单细胞转录组学表明，界面细胞采用了神经元侵袭的基因程序，包括获得在迁移过程中保护核核的乙酰化小管蛋白笼。

研究组确定了DNA弯曲蛋白HMGB2作为监禁诱导的神经元状态的介质。HMGB2在封闭的细胞中上调，定量模型显示封闭延长了HMGB2与染色质之间的接触时间，导致染色质结构的变化，有利于神经元表型。HMGB2的遗传破坏表明，它调节增殖和侵袭状态之间的权衡，在这种状态下，受限的HMGB2高的肿瘤细胞增殖能力较低，但耐药能力更强。他们的结果暗示机械微环境是驱动黑色素瘤表型转换的机制。

据介绍，表型转换是细胞可塑性的一种形式，其中癌细胞可逆地在两个相反的极端之间移动：增殖状态和侵袭状态。尽管长期以来人们一直假设这种转换是由外部线索触发的，但这些线索的身份仍不清楚。

附：英文原文

Title: Mechanical confinement governs phenotypic plasticity in melanoma

Author: Hunter, Miranda V., Joshi, Eshita, Bowker, Sydney, Montal, Emily, Ma, Yilun, Kim, Young Hun, Yang, Zhifan, Tuffery, Laura, Li, Zhuoning, Rosiek, Eric, Browning, Alexander, Moncada, Reuben, Yanai, Itai, Byrne, Helen, Monetti, Mara, de Stanchina, Elisa, Hamard, Pierre-Jacques, Koche, Richard P., White, Richard M.

Issue&Volume: 2025-08-27

Abstract: Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.

DOI: 10.1038/s41586-025-09445-6

Source: https://www.nature.com/articles/s41586-025-09445-6