Immune regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells

Newman, A. C., Falcone, M. , Huerta Uribe, A. , Zhang, T., Athineos, D., Pietzke, M., Vazquez, A. , Blyth, K. and Maddocks, O. D. K. (2021) Immune regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells. Molecular Cell, 81(11), 2290-2302.e7. (doi: 10.1016/j.molcel.2021.03.019) (PMID:33831358)

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Abstract

Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.

Item Type:Articles
Additional Information:We thank Biological Services facility staff at the Cancer Research UK Beatson Institute, funded by CRUK (A18076 and A17196), and Colin Nixon and Gemma Thomson for assistance with IHC and ISH. A.C.N., O.D.K.M., A.H.U. and T.Z. were funded by a Cancer Research UK Career Development Fellowship awarded to O.D.K.M. (C53309/A19702). M.F. was funded by an EMBO Long Term Fellowship (EMBO ALTF 276-2019). K.B. and D.A. were core funded by CRUK (A17196 and A29799). MP, AV, were funded by Cancer Research UK.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Maddocks, Professor Oliver and Newman, Dr Alice and Vazquez, Alexei and Huerta Uribe, Mr Alejandro and Zhang, Mr Tong and Athineos, Mr Dimitris and Falcone, Dr Mattia
Authors: Newman, A. C., Falcone, M., Huerta Uribe, A., Zhang, T., Athineos, D., Pietzke, M., Vazquez, A., Blyth, K., and Maddocks, O. D. K.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Molecular Cell
Publisher:Elsevier (Cell Press)
ISSN:1097-2765
ISSN (Online):1097-4164
Published Online:07 April 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Molecular Cell 81(11): 2290-2302.e7
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190874CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)C596/A18076Institute of Cancer Sciences
171982Targeting Tumour Metabolism for Cancer Therapy and Diagnosis.Oliver MaddocksCancer Research UK (CRUK)C53309/A19702Institute of Cancer Sciences