Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer
Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo. These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies.
Authors
- Lok Ting Lau (ORCID: https://orcid.org/0000-0001-7517-1486)
- S Shathishwaran
- Weiping Han (ORCID: https://orcid.org/0000-0002-5023-2104)
- Tony Kiat Hon Lim (ORCID: https://orcid.org/0000-0003-0645-5164)
- E.H. Tan (ORCID: https://orcid.org/0009-0005-2750-0472)
- Kai Lay Esther Peh (ORCID: https://orcid.org/0000-0001-5622-8870)
- Zhengwei Wu (ORCID: https://orcid.org/0000-0001-9229-6176)
- Xun Hui Yeo (ORCID: https://orcid.org/0000-0002-2787-5320)
- Anders J. Skanderup (ORCID: https://orcid.org/0000-0001-6847-4980)
- Yin Ying Ho (ORCID: https://orcid.org/0000-0002-5154-9605)
- Ying Swan Ho (ORCID: https://orcid.org/0000-0002-9292-3106)
- Daniel S.W. Tan (ORCID: https://orcid.org/0000-0002-6514-6786)
- Ju Yuan
- Jessica A. Lidster (ORCID: https://orcid.org/0000-0002-3003-0900)
- Wai Leong Tam (ORCID: https://orcid.org/0000-0003-2365-5264)
- Angela Takano (ORCID: https://orcid.org/0000-0002-7830-8430)
- Seow Q. Ng (ORCID: https://orcid.org/0000-0001-8391-7233)
- Zi Jin Cheryl Phua
- Paul Schwerd‐Kleine
- Ying Zhang (ORCID: https://orcid.org/0000-0002-2563-5606)
- Zhenxun Wang (ORCID: https://orcid.org/0000-0002-7862-4636)
- Vinay Tergaonkar (ORCID: https://orcid.org/0009-0009-4052-8620)
- Yui Hei Jasper Chiu
Institutions
- Agency for Science, Technology and Research (SG)
- Singapore General Hospital (SG)
- Singapore National Eye Center (SG)
- National University Cancer Institute, Singapore (SG)
- Singapore Eye Research Institute (SG)
- National Cancer Centre Singapore (SG)
- Bioprocessing Technology Institute (SG)
- Genome Institute of Singapore (SG)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-10-24
- DOI
- https://doi.org/10.1016/j.cmet.2025.10.001
- Citations
- 1
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 1.16