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Harnessing metabolic dependencies in pancreatic cancers

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of <10%. The tumour microenvironment (TME) of PDAC is characterized by excessive fibrosis and deposition of extracellular matrix, termed desmoplasia. This unique TME leads to high interstitial pressure, vascular collapse and low nutrient and oxygen diffusion. Together, these factors contribute to the unique biology and therapeutic resistance of this deadly tumour. To thrive in this hostile environment, PDAC cells adapt by using non-canonical metabolic pathways and rely on metabolic scavenging pathways such as autophagy and macropinocytosis. Here, we review the metabolic pathways that PDAC use to support their growth in the setting of an austere TME. Understanding how PDAC tumours rewire their metabolism and use scavenging pathways under environmental stressors might enable the identification of novel therapeutic approaches.

Key points

  • Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia, low nutrient levels, high interstitial pressure and desmoplasia.

  • To survive and thrive in this hostile environment, PDAC cells reprogramme their metabolism.

  • PDAC cells also utilize lysosomal scavenging pathways (for example, autophagy and macropinocytosis) to support and maintain metabolic homeostasis.

  • Other cellular populations present in the tumour microenvironment of PDAC, such as cancer-associated fibroblasts, neurons and immune cells, can support PDAC growth under nutrient-limiting conditions.

  • Targeting the metabolic vulnerabilities of PDAC could provide new therapeutic interventions.

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Fig. 1: Metabolic alterations in pancreatic cancers22.
Fig. 2: Pancreatic cancers rely on autophagy and lysosomal scavenging.

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Acknowledgements

We apologize for the omission of any primary citations. We thank members of the laboratory of A.C.K. for helpful discussion and thoughtful suggestions. The authors are supported by National Cancer Institute Grants, R35CA232124, P01CA117969 and P30CA016087, and the Lustgarten Foundation, and SU2C to A.C.K. and HHMI Gilliam Fellowships for Advanced Study to J.E.-R.

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Correspondence to Alec C. Kimmelman.

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A.C.K. has financial interests in Vescor Therapeutics and is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagic control of iron metabolism. A.C.K. is on the scientific advisory board of Rafael/Cornerstone Pharmaceuticals and is a consultant for Deciphera and Abbvie. The other author declares no competing interests.

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Nature Reviews Gastroenterology & Hepatology thanks H. Crawford, R. DeBerardinis, R. Perera and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Encarnación-Rosado, J., Kimmelman, A.C. Harnessing metabolic dependencies in pancreatic cancers. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00431-7

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