Journal
NATURE
Volume 536, Issue 7617, Pages 479-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature19084
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Categories
Funding
- NIH [5P30CA06516, GM095567, DK097153]
- NCI [R01CA157490, R01CA188048]
- ACS [RSG-13-298-01-TBG]
- Lustgarten Foundation
- PanCAN-AACRPathway to Leadership award
- Dale F. Frey award from Damon Runyon Cancer Research Foundation [DFS-09-14]
- PanCAN-AACR
- Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0509]
- [P01CA117969]
- [P30CA006516]
- [P01CA120964]
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism(1-4). 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(5-10). The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment(4,11,12). As such, these tumours must alter how they capture and use nutrients to support their metabolic needs(11,13). 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(4,11). 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.
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