Dynamics of nevus development implicate cell cooperation in the growth arrest of transformed melanocytes.
Dynamics of nevus development implicate cell cooperation in the growth arrest of transformed melanocytes.
复制标题
黑素细胞转化后的生长停滞与黑色素细胞的细胞协作有关。
DOI：
10.7554/elife.61026
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发表时间：
2020-10-13
期刊：
影响因子：
7.7
通讯作者：
Lander AD
中科院分区：
文献类型：
--
作者：
Ruiz-Vega R;Chen CF;Razzak E;Vasudeva P;Krasieva TB;Shiu J;Caldwell MG;Yan H;Lowengrub J;Ganesan AK;Lander AD
黑色素细胞中BRAF原癌基因的突变激活可靠地产生良性痣（色素“痣”），但相同的变化是黑色素瘤中最常见的驱动突变。痣停止生长而不发展为黑色素瘤的原因，被广泛归因于“癌基因诱导的衰老”的细胞自主过程。使用braf驱动的痣形成的小鼠模型，分析增殖动力学和单细胞基因表达，我们没有发现痣细胞衰老的证据，无论是与其他皮肤细胞还是其他黑色素细胞相比。我们还发现，痣的大小分布不能被任何简单的细胞自主生长停滞模型拟合，但很容易被基于集体细胞行为的模型拟合，例如，在这些模型中，停滞细胞释放一种促进停滞的因子。我们认为，痣生长停滞更可能与正常组织中调节大小控制的细胞相互作用有关，而不是与任何细胞自主的“癌基因诱导的”衰老程序有关。黑素细胞是遍布皮肤的色素生成细胞。激活BRAF基因的突变会导致这些细胞分裂并产生黑素细胞痣，也被称为“痣”。这些突变是致癌的，也就是说它们会致癌。事实上，BRAF是黑色素瘤中最常见的突变基因，黑色素瘤是一种由黑色素细胞引起的致命皮肤癌。然而，痣几乎不会发展成黑色素瘤。对这种行为的一种解释是，BRAF一旦被激活，就会在每个黑素细胞中启动一个称为“癌基因诱导衰老”的过程。这一过程被比作早衰，被认为是导致痣内细胞停止分裂的原因。虽然这一假设被广泛接受，但事实证明很难直接验证。为了研究这一观点，Ruiz-Vega等人研究了数百只由人类痣中发现的相同BRAF突变产生的痣的小鼠。分析单个细胞的基因活性显示，停止生长的痣黑色素细胞并不比其他皮肤细胞衰老，包括非痣黑色素细胞。Ruiz-Vega等人随后分析了痣停止生长的大小，估计了每个痣中的细胞数量。然后将数据与模拟和数学建模的结果进行比较。这表明，任何基于细胞在一系列随机事件后独立关闭的想法的模型都不能再现实验观察到的摩尔大小分布。另一方面，基于黑素细胞集体停止彼此生长的模型更符合观察到的数据。这些发现表明，痣的生长并不是BRAF激活的直接结果，而是因为它们能感知并对自身的过度生长做出反应。在保持恒定大小的正常组织中也观察到同样的集体感应。发现黑素细胞这样做不仅揭示了痣停止生长的原因，还可以帮助研究人员设计出防止黑素瘤形成的新方法。
Mutational activation of the BRAF proto-oncogene in melanocytes reliably produces benign nevi (pigmented ‘moles’), yet the same change is the most common driver mutation in melanoma. The reason nevi stop growing, and do not progress to melanoma, is widely attributed to a cell-autonomous process of ‘oncogene-induced senescence’. Using a mouse model of Braf-driven nevus formation, analyzing both proliferative dynamics and single-cell gene expression, we found no evidence that nevus cells are senescent, either compared with other skin cells, or other melanocytes. We also found that nevus size distributions could not be fit by any simple cell-autonomous model of growth arrest, yet were easily fit by models based on collective cell behavior, for example in which arresting cells release an arrest-promoting factor. We suggest that nevus growth arrest is more likely related to the cell interactions that mediate size control in normal tissues, than to any cell-autonomous, ‘oncogene-induced’ program of senescence. Melanocytes are pigment-producing cells found throughout the skin. Mutations that activate a gene called BRAF cause these cells to divide and produce melanocytic nevi, also known as “moles”. These mutations are oncogenic, meaning they can cause cancer. Indeed, BRAF is the most commonly mutated gene in melanoma, a deadly skin cancer that arises from melanocytes. Yet, moles hardly ever progress to melanoma. A proposed explanation for this behavior is that, once activated, BRAF initiates a process called “oncogene-induced senescence” in each melanocyte. This process, likened to premature aging, is thought to be what causes cells in a mole to quit dividing. Although this hypothesis is widely accepted, it has proved difficult to test directly. To investigate this notion, Ruiz-Vega et al. studied mice with hundreds of moles created by the same BRAF mutation found in human moles. Analyzing the activity of genes in individual cells revealed that nevus melanocytes that have stopped growing are no more senescent than other skin cells, including non-mole melanocytes. Ruiz-Vega et al. then analyzed the sizes at which moles stopped growing, estimating the number of cells in each mole. The data were then compared with the results of a simulation and mathematical modeling. This revealed that any model based on the idea of cells independently shutting down after a number of random events could not reproduce the distribution of mole sizes that had been experimentally observed. On the other hand, models based on melanocytes acting collectively to shut down each other’s growth fit the observed data much better. These findings suggest that moles do not stop growing as a direct result of the activation of BRAF, but because they sense and respond to their own overgrowth. The same kind of collective sensing is observed in normal tissues that maintain a constant size. Discovering that melanocytes do this not only sheds light on why moles stop growing, it could also help researchers devise new ways to prevent melanomas from forming.