Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion

Cristovão M. Sousa, Douglas E. Biancur, Xiaoxu Wang, Christopher J. Halbrook, Mara Sherman, Li Zhang, Daniel Kremer, Rosa F. Hwang, Agnes K. Witkiewicz, Haoqiang Ying, John M. Asara, Ronald M. Evans, Lewis C. Cantley, Costas A. Lyssiotis, Alec C. Kimmelman

Research output: Contribution to journalArticle

314 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)479-483
Number of pages5
JournalNature
Volume536
Issue number7617
DOIs
StatePublished - Aug 10 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)
  • General

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    Sousa, C. M., Biancur, D. E., Wang, X., Halbrook, C. J., Sherman, M., Zhang, L., Kremer, D., Hwang, R. F., Witkiewicz, A. K., Ying, H., Asara, J. M., Evans, R. M., Cantley, L. C., Lyssiotis, C. A., & Kimmelman, A. C. (2016). Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature, 536(7617), 479-483. https://doi.org/10.1038/nature19084