LKB1 Inactivation Elicits a Redox Imbalance to Modulate Non-small Cell Lung Cancer Plasticity and Therapeutic Response
Open accessAbstract
LKB1 regulates both cell growth and energy metabolism. It remains unclear how LKB1 inactivation coordinates tumor progression with metabolic adaptation in non-small cell lung cancer (NSCLC). Here in Kras(G12D);Lkb1(lox/lox) (KL) mouse model, we reveal differential reactive oxygen species (ROS) levels in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ROS can modulate ADC-to-SCC transdifferentiation (AST). Further, pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect AST. Similar tumor and redox heterogeneity also exist in human NSCLC with LKB1 inactivation. In preclinical trials toward metabolic stress, certain KL ADC can develop drug resistance through squamous transdifferentiation. This study uncovers critical redox control of tumor plasticity that may affect therapeutic response in NSCLC.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LKB1 loss promotes tumorigenesis by reprogramming epigenetic states, facilitating lineage plasticity and promoting metastasis.
“Beyond its role regulating metabolism via AMPK, LKB1 loss promotes tumorigenesis by reprogramming epigenetic states, facilitating lineage plasticity and promoting metastasis22,67–70.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [67]
The Abstract and Discussion report that LKB1 inactivation promotes lung-tumor plasticity, including adenocarcinoma-to-squamous transdifferentiation, and coordinates tumor progression with metabolic adaptation. The Introduction also describes accelerated progression in a Kras-mutant mouse model. Our copy does not establish epigenetic-state reprogramming as the mechanism or demonstrate increased metastasis; metastasis appears in the title of a cited study in the References. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn KRAS-driven lung adenocarcinoma, LKB1 loss often induces KEAP1 activation and metabolic alterations that can be counteracted by NRF2 activation, maintaining redox homeostasis and fueling glutamine-dependent energy metabolism.
“Moreover, in oncogenic-KRAS-driven lung adenocarcinoma, loss of LKB1 often induces KEAP1 activation69 and leads to metabolic alterations that could be counteracted by activation of NRF270, thereby maintaining redox homeostasis and fueling energy metabolism in a glutamine-dependent manner.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [70]
Loss of Lkb1 results in epigenetic reprogramming and an expanded tumor histological repertoire, with high incidence of squamous or adenosquamous carcinomas, in agreement with data supporting enrichment of LKB1 mutations in human adenosquamous NSCLC.
“In addition, loss of Lkb1 results in epigenetic reprogramming and an expanded tumor histological repertoire, with high incidence of squamous or adenosquamous carcinomas, in agreement with data supporting enrichment of LKB1 mutations in human adenosquamous NSCLC84–86.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [85]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 57 · Cited by 169
- Authors
- Li, F., Han, X., Li, F., Wang, R., Wang, H., Gao, Y., Wang, X., Fang, Z., Zhang, W., Yao, S., Tong, X., Wang, Y., Feng, Y., Sun, Y., Li, Y., Wong, K.-K., Zhai, Q., Chen, H., & Ji, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Fudan University Shanghai Cancer Center (CN)
- Tongji University (CN)
- Harvard University (US)
- Corresponding author
- Chen, Haiquan
- Ji, Hongbin
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 27
- Issue
- 5
- Pages
- 698-711
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4746728
- OpenAlex
- W2037920327
- Cited by
- 169
- References
- 57
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 19 · 2022: 10 · 2021: 29 · 2020: 19 · 2019: 19 · 2018: 12 · 2017: 9 · 2016: 12 · 2015: 2
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA166480, R01CA140594, R01CA163896)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- non-small cell lung cancer, reactive oxygen species, redox imbalance, tumor plasticity, squamous cell carcinoma, lung adenocarcinoma, pentose phosphate pathway, fatty acid oxidation, metabolic adaptation, KRAS G12D, drug resistance, tumor heterogeneity
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cell Differentiation, Disease Models, Animal, Humans, Lung Neoplasms, Oxidation-Reduction, Pentose Phosphate Pathway, Protein Serine-Threonine Kinases, Reactive Oxygen Species, Mice, AMP-Activated Protein Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
