Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion

By C. Sousa, D. Biancur, Xiaoxu Wang, Christopher J. Halbrook, M. Sherman, Li Zhang, Daniel M. Kremer, R. Hwang, Agnes K. Witkiewicz, Haoqiang Ying and 5 more. Nature, 2016

1,001 citations recorded by the source corpus.

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.

Subfields: Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/6ed33b6c25c025e1722a8a0a60aa31ed92fa9311

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

In Surgery

Citations in the corpus

Autophagy-Independent Functions of the Autophagy Machinery (2019, neutral): “coremetabolism (Heet al., 2012; Sousa et al., 2016), damagecontrol (Fernández et al.”
Metabolic Interactions in the Tumor Microenvironment (2017, background): “This observation led to the finding that lung CAFs exhibit a high degree of basal autophagy, and together with the work on alanine release from pancreatic CAFs [58], suggest that autophagy is a major mechanism by which nutrients are transferred from CAFs to feed cancer cells in a tumor.”
Understanding the intersections between metabolism and cancer biology (2017, neutral): “Alanine produced by pancreatic stellate cells can promote pancreatic cancer cell proliferation (Sousa et al., 2016) and bone marrow stromal cells provide cysteine to promote survival of chronic lymphocytic leukemia cells (Zhang et al.”
Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research (2022, background): “This change in fuel source reduced the tumor cell reliance on glucose and nutrients obtained from serum, which are limited in the pancreatic TME [210].”
Metabolic reprogramming and cancer progression (2020, background): “Oncogene-driven expression of nutrient transporters (24, 50), the ability to derive energy from diverse nutrient sources—including scavenged protein, recycled organelles, and necrotic debris (51–54)—and metabolic cooperativity among cancer cells or between cancer cells and stromal cells (55, 56) lik”
Mitochondrial metabolism and cancer (2017, background): “Along similar lines, PDAC cells drive TAFs into autophagic responses that ultimately sustain tumor growth by increasing the local availability of alanine (employed by cancer cells as a carbon source) [130].”
Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy (2022, background): “Pancreatic stellate cells secrete alanine through autophagy by pancreatic tumor cells to promote growth-friendly mitochondrial metabolism.(69)”
Autophagy and Tumor Metabolism (2017, background): “While the aforementioned studies have focused predominantly on the direct contribution of autophagy to the metabolism in the tumor cell itself, several studies have also shown a critical impact of autophagy on tumor growth in a cell non-autonomous manner and in many cases this is related to effects ”