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Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion.

Date Posted: February 8, 2017

TitlePancreatic stellate cells support tumour metabolism through autophagic alanine secretion.
Publication TypeJournal Article
Year of Publication2016
AuthorsSousa 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
JournalNature
Volume536
Issue7617
Pagination479-83
Date Published2016 Aug 25
ISSN1476-4687
KeywordsAdenocarcinoma, Alanine, Animals, Autophagy, Biosynthetic Pathways, Carbon, Carcinoma, Pancreatic Ductal, Citric Acid Cycle, Female, Glucose, Heterografts, Humans, Mice, Neoplasm Transplantation, Pancreatic Neoplasms, Pancreatic Stellate Cells, Tumor Microenvironment
Abstract

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.

DOI10.1038/nature19084
Alternate JournalNature
PubMed ID27509858
PubMed Central IDPMC5228623
Grant ListGM095567 / GM / NIGMS NIH HHS / United States
P30 CA016672 / CA / NCI NIH HHS / United States
R01CA188048 / CA / NCI NIH HHS / United States
P30 CA046592 / CA / NCI NIH HHS / United States
P01 CA117969 / CA / NCI NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P30CA006516 / CA / NCI NIH HHS / United States
R01 CA157490 / CA / NCI NIH HHS / United States
R01 GM095567 / GM / NIGMS NIH HHS / United States
P01CA117969 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
DK097153 / DK / NIDDK NIH HHS / United States
R01CA157490 / CA / NCI NIH HHS / United States
R37 DK057978 / DK / NIDDK NIH HHS / United States
5P30CA06516 / CA / NCI NIH HHS / United States
P01CA120964 / CA / NCI NIH HHS / United States
U24 DK097153 / DK / NIDDK NIH HHS / United States
R01 CA188048 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
P30 CA014195 / CA / NCI NIH HHS / United States