Editors' ChoiceCancer Metabolism

PDAC puts its neighbors to work

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Sci. Signal.  30 Aug 2016:
Vol. 9, Issue 443, pp. ec198
DOI: 10.1126/scisignal.aai8922

Cell survival and proliferation requires metabolic activity that depends on oxygen and nutrients, such as amino acids and glucose. Pancreatic ductal adenocarcinoma (PDAC) is characterized by progressive inflammation and fibrotic desmoplasia, which impedes the tumor’s blood supply and creates a nutrient-poor environment yet paradoxically promotes the growth of the tumor. When nutrients are scarce, cells initiate a process called autophagy, in which cells break down nonessential proteins, lipids, and other macromolecules for use as biosynthetic metabolites. Autophagy is a survival mechanism for many types of nutrient-starved tumors. However, Sousa et al. (see also Kamphorst and Gottlieb) found that PDAC growth was supported by scavenging a key nutrient secreted from pancreatic stellate cells (PSCs) undergoing autophagy in the surrounding stroma. When cultured with conditioned media from various PSC lines, 8988T PDAC cells, but not nonmalignant pancreatic ductal epithelial cells, had increased oxygen consumption, a marker of mitochondrial activity. PSC-conditioned medium increased PDAC cell proliferation in low-serum conditions. Repeat freeze-thaw cycles and filtration of the PSC-conditioned medium suggested that the critical molecule for this increased proliferation was small and had a nontertiary structure (meaning, not a protein). Metabolomic profiling of medium conditioned by PSCs before and after contact with PDAC cells and of PDAC cells treated with PSC-conditioned medium identified the metabolite transferred from PSCs to PDAC cells as the nonessential amino acid alanine. These results were confirmed by functional testing in cultured cells. Metabolic tracing experiments using heavy carbon-isotope labeling revealed that PSC-derived alanine was taken up by PDAC cells and transported to the mitochondria, where it underwent transamination (removal of nitrogen). Through transamination, alanine provides an alternate source to glucose for the generation of pyruvate, a key molecule with which mitochondria produce ATP and other metabolites. Knocking down the alanine transaminases GPT1 and GPT2 in PDAC cells increased the intracellular accumulation of alanine and decreased oxygen consumption in PDAC cells cultured in PSC-conditioned medium. Glucose-derived carbon tracing indicated that alanine was used selectively in the mitochondria, did not disrupt cytosolic glycolysis, and increased serine biosynthesis, suggesting that alanine uptake enabled the reallocation of glucose to other metabolic processes, such as nucleic acid synthesis. PSCs cultured with PDAC cells or in PDAC-conditioned medium had increased autophagic flux. Knocking down the autophagy proteins ATG5 and ATG7 in PSCs did not affect PSC survival but did prevent the ability of PSC-conditioned medium to increase oxygen consumption in PDAC cells, except when exogenous alanine was applied. In vivo experiments in which PDAC cells and PSCs were coinjected into mice recapitulated the cell culture findings. These findings suggest that PDAC cells secrete a signal that induces autophagy in PSCs to secrete alanine and is another example of reciprocal communication between PDAC and PSCs.

C. M. Sousa, D. E. Biancur, X. Wang, C. J. Halbrook, M. H. Sherman, L. Zhang, D. Kremer, R. F. Hwang, A. K. Witkiewicz, H. Ying, J. M. Asara, R. M. Evans, L. C. Cantley, C. A. Lyssiotis, A. C. Kimmelman, Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016). [PubMed]

J. J. Kamphorst, E. Gottlieb, Friendly neighbours feed tumour cells. Nature 536, 401–402 (2016). [PubMed]