Cited by 22Lung Cancer Research StudiesLung Cancer Treatments and MutationsCancer Cells and Metastasis

LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer

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Murray, Christopher W., Brady, Jennifer J., Han, Mingqi, Cai, Hongchen, Tsai, Min K., Pierce, Sarah E., Cheng, Ran, Demeter, Janos +4 more·2022·Nature Communications

Abstract

LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPα, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.

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Crossref · 10.1038/s41467-022-28619-8

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  • 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 [70]

    The Introduction reports that Lkb1 deletion accelerates lung tumor growth, and the Results describe loss of alveolar type II differentiation and the emergence of other neoplastic cell states after Lkb1 inactivation. The Discussion says inactivation imparts epigenetic plasticity, but calls for further study of its mechanisms. This paper does not establish that LKB1 loss promotes metastasis; it discusses testing Lkb1 restoration within metastases as future work. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Authors
Murray, C. W., Brady, J. J., Han, M., Cai, H., Tsai, M. K., Pierce, S. E., Cheng, R., Demeter, J., Feldser, D. M., Jackson, P. K., Shackelford, D. B., & Winslow, M. M.
Affiliations
  • Stanford Medicine (US)
  • University of California, Los Angeles (US)
  • University of Pennsylvania (US)
Corresponding author
Winslow, Monte M.
Venue
Nature Communications
Published
2022-02-28
Volume
13
Issue
1
Pages
1090-1090
ISSN
2041-1723 (ISSN-L)
OpenAlex
W4214768247
Cited by
22
References
146
Citations by year
2026: 4 · 2025: 8 · 2024: 5 · 2023: 3 · 2022: 2
FWCI
1.88
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (NIH R01-CA175336, NIH R01-CA207133, NIH R01-CA230919, NIH F32-CA189659, NIH R01-CA208642)
  • U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIH 5T32GM007276)
  • U.S. Department of Defense (LCRP W81XWH-18-1-0295)
Topics
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
LKB1, lung adenocarcinoma, C/EBP transcription factors, C/EBPα, TTF-1, lineage reprogramming, tumor suppressor restoration, oncogenic KRAS, tumor differentiation
MeSH terms
Animals, Lung Neoplasms, Transcription Factors, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Cell Line, Tumor, Mice, AMP-Activated Protein Kinases, Carcinogenesis

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