Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion

• Published in: Nature (London) Vol. 536; no. 7617; pp. 479 - 483
• Main Authors: Sousa, Cristovão M., Biancur, Douglas E., Wang, Xiaoxu, Halbrook, Christopher J., Sherman, Mara H., Zhang, Li, Kremer, Daniel, Hwang, Rosa F., Witkiewicz, Agnes K., Ying, Haoqiang, Asara, John M., Evans, Ronald M., Cantley, Lewis C., Lyssiotis, Costas A., Kimmelman, Alec C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.08.2016; Nature Publishing Group
• Subjects: 13/106; 13/51; 13/89; 14/63; 631/67/2327; 631/67/327; 64/110; 64/60; 82/1; 82/58; 82/80; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Alanine; Alanine - metabolism; Amino acids; Animals; Autophagy; Biosynthesis; Biosynthetic Pathways; Carbon; Carbon - metabolism; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Citric Acid Cycle; Female; Glucose - metabolism; Health aspects; Heterografts; Humanities and Social Sciences; Humans; Hypoxia; letter; Metabolism; Metabolites; Mice; multidisciplinary; Neoplasm Transplantation; Nutrients; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Pancreatic Stellate Cells - cytology; Pancreatic Stellate Cells - metabolism; Physiological aspects; Science; Tumor Microenvironment - physiology; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature19084

Pancreatic adenocarcinoma cells drive autophagy in tumour microenvironment-associated stellate cells, which release alanine that is used by the cancer cells as a carbon source for a variety of metabolic processes in an otherwise nutrient-poor environment. A cancer cell support network dissected Cancer cells generally have metabolic needs that differ from those of neighbouring normal cells, and hence display rewired metabolic networks. Cristovão Sousa et al . show that, in pancreatic cancers, stellate cells in the tumour environment supply cancer cells with the amino acid alanine as the carbon needed for anabolic processes when other sources are scarce. Tumour cells in turn stimulate autophagy in stellate cells, which is needed for alanine secretion. This cross-talk allows pancreatic cancer cells to fulfil their metabolic requirements in an environment lacking in other essential nutrients. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism 1 , 2 , 3 , 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 , 6 , 7 , 8 , 9 , 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.