Glycogen drives tumour initiation and progression in lung adenocarcinoma

Harrison A. Clarke; Tara R. Hawkinson; Cameron J. Shedlock; Terrymar Medina; Roberto A. Ribas; Lei Wu; Zizhen Liu; Xin Ma; Yi Xia; Yu Huang; Xing He; Josephine E. Chang; Lyndsay E.A. Young; Jelena A. Juras; Michael D. Buoncristiani; Alexis N. James; Anna Rushin; Matthew E. Merritt; Annette Mestas; Jessica F. Lamb; Elena C. Manauis; Grant L. Austin; Li Chen; Pankaj K. Singh; Jiang Bian; Craig W. Vander Kooi; B. Mark Evers; Christine F. Brainson; Derek B. Allison; Matthew S. Gentry; Ramon C. Sun

doi:10.1038/s42255-025-01243-8

Glycogen drives tumour initiation and progression in lung adenocarcinoma

Harrison A. Clarke, Tara R. Hawkinson, Cameron J. Shedlock, Terrymar Medina, Roberto A. Ribas, Lei Wu, Zizhen Liu, Xin Ma, Yi Xia, Yu Huang, Xing He, Josephine E. Chang, Lyndsay E.A. Young, Jelena A. Juras, Michael D. Buoncristiani, Alexis N. James, Anna Rushin, Matthew E. Merritt, Annette Mestas, Jessica F. LambElena C. Manauis, Grant L. Austin, Li Chen, Pankaj K. Singh, Jiang Bian, Craig W. Vander Kooi, B. Mark Evers, Christine F. Brainson, Derek B. Allison, Matthew S. Gentry, Ramon C. Sun

Research output: Contribution to journal › Article › peer-review

Abstract

Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.

Original language	English
Article number	e44235
Pages (from-to)	952-965
Number of pages	14
Journal	Nature Metabolism
Volume	7
Issue number	5
DOIs	https://doi.org/10.1038/s42255-025-01243-8
State	Published - May 2025

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature Limited 2025.

Funding

This study was supported by National Institute of Health (NIH) grants R01AG066653, R01CA266004, R01AG078702, R01CA288696, V-Scholar Grant, and RM1NS133593 to R.C.S., R35NS116824 to M.S.G., R35GM142701 to L.C., T32HL134621 to H.A.C., and R01CA237643 and P20GM121327-03 to C.F.B. This research was also supported by the Biospecimen Procurement and Translational Pathology Shared Resource Facility of the University of Kentucky Markey Cancer Center (P30CA177558) to D.B.A. and supported in part by an NIH award, S10 OD030293, for MRI/S instrumentation. Z.L. is supported by the MBI Gator NeuroScholar Program. Large language models, for example, ChatGPT, were used to make minor grammatical improvements in the text. We thank N. R. Gough (BioSerendipity, LLC) for critical discussions and editorial assistance.

Funders	Funder number
National Institutes of Health (NIH)	R35GM142701, R01AG078702, P20GM121327-03, R35NS116824, T32HL134621, R01CA288696, R01CA266004, R01AG066653, R01CA237643, RM1NS133593
National Institutes of Health (NIH)
University of Kentucky Markey Cancer Center	P30CA177558, S10 OD030293
University of Kentucky Markey Cancer Center

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism
Physiology (medical)
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s42255-025-01243-8

Cite this

Clarke, H. A., Hawkinson, T. R., Shedlock, C. J., Medina, T., Ribas, R. A., Wu, L., Liu, Z., Ma, X., Xia, Y., Huang, Y., He, X., Chang, J. E., Young, L. E. A., Juras, J. A., Buoncristiani, M. D., James, A. N., Rushin, A., Merritt, M. E., Mestas, A., ... Sun, R. C. (2025). Glycogen drives tumour initiation and progression in lung adenocarcinoma. Nature Metabolism, 7(5), 952-965. Article e44235. https://doi.org/10.1038/s42255-025-01243-8

@article{61aa5f06050049ebbd450301fba5c0fb,

title = "Glycogen drives tumour initiation and progression in lung adenocarcinoma",

abstract = "Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.",

author = "Clarke, \{Harrison A.\} and Hawkinson, \{Tara R.\} and Shedlock, \{Cameron J.\} and Terrymar Medina and Ribas, \{Roberto A.\} and Lei Wu and Zizhen Liu and Xin Ma and Yi Xia and Yu Huang and Xing He and Chang, \{Josephine E.\} and Young, \{Lyndsay E.A.\} and Juras, \{Jelena A.\} and Buoncristiani, \{Michael D.\} and James, \{Alexis N.\} and Anna Rushin and Merritt, \{Matthew E.\} and Annette Mestas and Lamb, \{Jessica F.\} and Manauis, \{Elena C.\} and Austin, \{Grant L.\} and Li Chen and Singh, \{Pankaj K.\} and Jiang Bian and \{Vander Kooi\}, \{Craig W.\} and Evers, \{B. Mark\} and Brainson, \{Christine F.\} and Allison, \{Derek B.\} and Gentry, \{Matthew S.\} and Sun, \{Ramon C.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2025.",

year = "2025",

month = may,

doi = "10.1038/s42255-025-01243-8",

language = "English",

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Clarke, HA, Hawkinson, TR, Shedlock, CJ, Medina, T, Ribas, RA, Wu, L, Liu, Z, Ma, X, Xia, Y, Huang, Y, He, X, Chang, JE, Young, LEA, Juras, JA, Buoncristiani, MD, James, AN, Rushin, A, Merritt, ME, Mestas, A, Lamb, JF, Manauis, EC, Austin, GL, Chen, L, Singh, PK, Bian, J, Vander Kooi, CW, Evers, BM , Brainson, CF , Allison, DB, Gentry, MS & Sun, RC 2025, 'Glycogen drives tumour initiation and progression in lung adenocarcinoma', Nature Metabolism, vol. 7, no. 5, e44235, pp. 952-965. https://doi.org/10.1038/s42255-025-01243-8

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AU - Clarke, Harrison A.

AU - Hawkinson, Tara R.

AU - Shedlock, Cameron J.

AU - Medina, Terrymar

AU - Ribas, Roberto A.

AU - Wu, Lei

AU - Liu, Zizhen

AU - Ma, Xin

AU - Xia, Yi

AU - Huang, Yu

AU - He, Xing

AU - Chang, Josephine E.

AU - Young, Lyndsay E.A.

AU - Juras, Jelena A.

AU - Buoncristiani, Michael D.

AU - James, Alexis N.

AU - Rushin, Anna

AU - Merritt, Matthew E.

AU - Mestas, Annette

AU - Lamb, Jessica F.

AU - Manauis, Elena C.

AU - Austin, Grant L.

AU - Chen, Li

AU - Singh, Pankaj K.

AU - Bian, Jiang

AU - Vander Kooi, Craig W.

AU - Evers, B. Mark

AU - Brainson, Christine F.

AU - Allison, Derek B.

AU - Gentry, Matthew S.

AU - Sun, Ramon C.

PY - 2025/5

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N2 - Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.

AB - Lung adenocarcinoma (LUAD) is an aggressive cancer defined by oncogenic drivers and metabolic reprogramming. Here we leverage next-generation spatial screens to identify glycogen as a critical and previously underexplored oncogenic metabolite. High-throughput spatial analysis of human LUAD samples revealed that glycogen accumulation correlates with increased tumour grade and poor survival. Furthermore, we assessed the effect of increasing glycogen levels on LUAD via dietary intervention or via a genetic model. Approaches that increased glycogen levels provided compelling evidence that elevated glycogen substantially accelerates tumour progression, driving the formation of higher-grade tumours, while the genetic ablation of glycogen synthase effectively suppressed tumour growth. To further establish the connection between glycogen and cellular metabolism, we developed a multiplexed spatial technique to simultaneously assess glycogen and cellular metabolites, uncovering a direct relationship between glycogen levels and elevated central carbon metabolites essential for tumour growth. Our findings support the conclusion that glycogen accumulation drives LUAD cancer progression and provide a framework for integrating spatial metabolomics with translational models to uncover metabolic drivers of cancer.

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Glycogen drives tumour initiation and progression in lung adenocarcinoma

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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