Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.
Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.
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DOI：
10.1038/nature19084
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发表时间：
2016-08-25
期刊：
影响因子：
64.8
通讯作者：
Kimmelman AC
中科院分区：
文献类型：
--
作者：
Sousa CM;Biancur DE;Wang X;Halbrook CJ;Sherman MH;Zhang L;Kremer D;Hwang RF;Witkiewicz AK;Ying H;Asara JM;Evans RM;Cantley LC;Lyssiotis CA;Kimmelman AC
胰腺导管腺癌（PDAC）是一种侵袭性疾病，其特征是强烈的纤维化基质反应和代谢失调。基质在PDAC生物学中的作用是复杂的，并且已经显示其根据生物学背景而发挥不同的关键作用。基质反应还损害血管系统，导致高度缺氧、营养不良的环境。因此，这些肿瘤必须改变它们如何捕获和使用营养物质来支持它们的代谢需求。在这里，我们表明，基质相关的胰腺星状细胞（PSC）是至关重要的PDAC代谢通过分泌非必需氨基酸（NEAA）。具体来说，我们发现了丙氨酸以前未描述的作用，它在PDAC中胜过葡萄糖和谷氨酰胺衍生的碳，为三羧酸（TCA）循环提供燃料，从而促进NEAA和脂质生物合成。这种燃料来源的转变降低了肿瘤对葡萄糖和血清来源的营养物质的依赖性，这些营养物质在胰腺肿瘤微环境中受到限制。此外，我们证明PSC的丙氨酸分泌依赖于PSC自噬，这是一个由癌细胞刺激的过程。因此，我们的研究结果证明了PSC和癌细胞之间的新的代谢相互作用，其中PSC衍生的丙氨酸作为替代碳源。这一发现突出了胰腺肿瘤内以前未被认识到的代谢网络，其中使用不同的燃料源来促进严峻的肿瘤微环境中的生长。
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism. The role of the stroma in PDAC biology is complex and it has been shown to play critical roles that differ depending on the biological context. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs. Here we show that stroma-associated pancreatic stellate cells (PSCs) are critical for PDAC metabolism through the secretion of non-essential amino acids (NEAA). Specifically, we uncover a previously undescribed role for alanine, which outcompetes glucose and glutamine-derived carbon in PDAC to fuel the tricarboxylic acid (TCA) cycle, and thus NEAA and lipid biosynthesis. This shift in fuel source decreases the tumour’s dependence on glucose and serum-derived nutrients, which are limited in the pancreatic tumour microenvironment. Moreover, we demonstrate that alanine secretion by PSCs is dependent on PSC autophagy, a process that is stimulated by cancer cells. Thus, our results demonstrate a novel metabolic interaction between PSCs and cancer cells, in which PSC-derived alanine acts as an alternative carbon source. This finding highlights a previously unappreciated metabolic network within pancreatic tumours in which diverse fuel sources are used to promote growth in an austere tumour microenvironment.