Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by an intense fibrotic stromal response and deregulated metabolism1,2,3,4. 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 context5,6,7,8,9,10. The stromal reaction also impairs the vasculature, leading to a highly hypoxic, nutrient-poor environment4,11,12. As such, these tumours must alter how they capture and use nutrients to support their metabolic needs11,13. 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 microenvironment4,11. 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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We thank Kimmelman laboratory members for reading the manuscript, A. Yang for help with orthotopic injections, M. Yuan and S. Breitkopf for technical support with mass spectrometry, E. Sicinska for resected PDAC specimens, and the Dana-Farber/Harvard Cancer Center Rodent Histopathology Core for assistance with tissue processing. DFHCC is supported in part by NIH 5P30CA06516. A.C.K. is supported by NIH grant GM095567, NCI grants R01CA157490, R01CA188048, ACS Research Scholar Grant (RSG-13-298-01-TBG), and the Lustgarten Foundation. C.A.L. is supported by a PanCAN-AACR Pathway to Leadership award and a Dale F. Frey award from the Damon Runyon Cancer Research Foundation (DFS-09-14). Metabolomics studies performed at the University of Michigan were supported by NIH grant DK097153. L.C.C. was supported by P01CA117969, PanCAN-AACR and the Lustgarten Foundation. J.M.A. was supported by P30CA006516 and P01CA120964. R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute, and is supported in part by grants from The Lustgarten Foundation and a Stand Up to Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0509).
Extended data figures
This file contains Supplementary Tables 1-4.