What’s on the menu?: metabolic constraints in the pancreatic tumor microenvironment
Colin Sheehan, Alexander Muir
Colin Sheehan, Alexander Muir
Published July 15, 2025
Citation Information: J Clin Invest. 2025;135(14):e191940. https://doi.org/10.1172/JCI191940.
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What’s on the menu?: metabolic constraints in the pancreatic tumor microenvironment

Abstract

The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is composed of a dense stromal compartment and is poorly vascularized, resulting in limited nutrient delivery. As a result, PDAC cells must adapt to cope with the metabolic stresses brought on by TME nutrient limitation. In this article, we first review recent studies that have provided quantitative measurements of nutrient levels in the PDAC TME. These studies have provided a new understanding of the nutrient limitations and metabolic stresses that occur in PDAC. We next discuss the adaptive strategies employed by PDAC in response to TME nutrient limitation. We propose that PDAC adaptations to metabolic stress can be generalized into four categories: (a) cutting down on metabolic costs by recycling metabolites and suppressing nonessential processes, (b) upregulating biosynthetic pathways to meet TME metabolic demands, (c) supporting essential metabolic processes with alternative fuel sources, and (d) dampening antiproliferative and cell death responses that nutrient limitation normally triggers. Improving our understanding of the nutrient limitations within the TME, and the adaptations cells employ to cope with these stresses, provides a more complete picture of PDAC biology and reveals new opportunities for therapeutic targeting of this disease.

Authors

Colin Sheehan, Alexander Muir

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Figure 2

PDAC adaptations to tumor nutrient stress.

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PDAC adaptations to tumor nutrient stress. (A) Reduce, reuse, recycle. N...
(A) Reduce, reuse, recycle. Nutrient-sensitive regulation allows PDAC to lower cap-dependent mRNA translation to spare amino acids. Reversal of ornithine aminotransferase (OAT) activity allows PDAC to spare limiting arginine. Recycling of macromolecules by autophagy allows PDAC to recapture and reuse metabolites like amino acids. (B) Make it yourself. De novo arginine and glutamine synthesis allows PDAC to cope with endogenous starvation of these amino acids in the TME. De novo asparagine and serine synthesis allow PDAC to cope with therapeutic starvation of these amino acids. (C) Never turn down a free lunch. Macropinocytosis allows PDAC to acquire amino acids from extracellular protein sources. Metabolic exchange of multiple nutrients with stromal cells can enable PDAC to overcome TME nutrient stress. (D) Become numb. Induction of ROS quenching processes, such as isocitrate dehydrogenase 1 (IDH1), allow PDAC to mitigate damage caused by nutrient stress. Dampening of apoptotic signaling allows PDAC to survive nutrient stress that cannot be overcome and would otherwise cause loss of cell viability. AKG, α-ketoglutarate; ARG1, arginase; ASL, arginosuccinate lyase; BAD, BCL-2 associated death promoter; GLS, glutaminase; GLUL, glutamate ammonia ligase; OAA, oxaloacetate; ODC, ornithine decarboxylase; p-BAD, phospho-BAD; P-5-C, pyrroline-5-carboxylate; P5CS, pyrroline-5-carboxylate synthase; PG, phosphoglycerate; PHGDH, phosphoglycerate dehydrogenase; PIM1, proto-oncogene serine/threonine-protein kinase; PS, phosphoserine; PSAT1, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; SCD1, stearoyl-CoA desaturase; tRNA, transfer RNA.