Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion

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.