Metabolic origins of spatial organization in the tumor microenvironment.
Metabolic origins of spatial organization in the tumor microenvironment.
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DOI：
10.1073/pnas.1700600114
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发表时间：
2017-03-14
影响因子：
11.1
通讯作者：
Xavier JB
中科院分区：
文献类型：
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作者：
Carmona-Fontaine C;Deforet M;Akkari L;Thompson CB;Joyce JA;Xavier JB
癌症表现为不同细胞的无序混合物，这也是它们难以治疗的部分原因。我们在这里表明，尽管存在这种混乱，肿瘤仍显示出大多数癌症常见的细胞过程中出现的局部组织：癌细胞代谢的改变以及与肿瘤微环境中基质细胞的相互作用。通过结合实验和计算机模拟的多学科方法，我们发现癌细胞的代谢活动产生营养物和代谢废物的梯度，这些梯度充当细胞用来了解其相对于血管的位置的信号。这种位置信息协调了肿瘤和基质细胞的模块化组织，类似于胚胎组织，我们可以将其用作治疗靶点。肿瘤内细胞的遗传和表型多样性是癌症治疗的主要障碍。由于遗传改变的随机性，这种肿瘤内异质性通常被认为是混乱的。在这里，我们表明癌细胞代谢的改变产生了可预测的细胞外代谢物梯度，从而协调了肿瘤微环境中细胞的表型多样性。结合实验和数学模型，我们发现肿瘤微环境中消耗和分泌的代谢物会根据局部缺血水平及其相对于脉管系统的位置诱导肿瘤相关巨噬细胞（TAM）分化成不同的亚群。 TAM 将缺氧和乳酸水平整合到 MAPK 信号传导的逐渐激活中，从而诱导可预测的基因表达空间模式，例如表达精氨酸酶 1 (ARG1) 和甘露糖受体 C 型 1 (MRC1) 的巨噬细胞条纹。这些表型变化在功能上是相关的，因为缺血性巨噬细胞触发邻近内皮细胞的管状形态发生，可以恢复最需要血管生成资源的营养匮乏区域的血液灌注。我们认为细胞外代谢物的梯度充当肿瘤形态发生素，在微环境中施加秩序，就像信号分子传递位置信息来组织胚胎组织一样。发掘肿瘤中类似胚胎学的过程可能使我们能够控制类似器官的肿瘤特征，例如组织修复和血运重建，并治疗肿瘤内异质性。
Cancers appear as disordered mixtures of different cells, which is partly why they are hard to treat. We show here that despite this chaos, tumors show local organization that emerges from cellular processes common to most cancers: the altered metabolism of cancer cells and the interactions with stromal cells in the tumor microenvironment. With a multidisciplinary approach combining experiments and computer simulations we revealed that the metabolic activity of cancer cells produces gradients of nutrients and metabolic waste products that act as signals that cells use to know their position with respect to blood vessels. This positional information orchestrates a modular organization of tumor and stromal cells that resembles embryonic organization, which we could exploit as a therapeutic target. The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity.