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Cited by 59Chromatin Remodeling and CancerCancer Cells and MetastasisGenomics and Chromatin Dynamics

LKB1 inactivation modulates chromatin accessibility to drive metastatic progression

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Pierce, Sarah E., Granja, Jeffrey M., Corces, M. Ryan, Brady, Jennifer J., Tsai, Min K., Pierce, Aubrey B., Tang, Rui, Chu, Pauline +5 more·2021·Nature Cell Biology
DOI 10.1038/s41556-021-00728-4PMC PMC8355205

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Abstract

Metastasis is the leading cause of cancer-related deaths and enables cancer cells to compromise organ function by expanding in secondary sites. Since primary tumours and metastases often share the same constellation of driver mutations, the mechanisms that drive their distinct phenotypes are unclear. Here we show that inactivation of the frequently mutated tumour suppressor gene LKB1 (encoding liver kinase B1) has evolving effects throughout the progression of lung cancer, which leads to the differential epigenetic re-programming of early-stage primary tumours compared with late-stage metastases. By integrating genome-scale CRISPR-Cas9 screening with bulk and single-cell multi-omic analyses, we unexpectedly identify LKB1 as a master regulator of chromatin accessibility in lung adenocarcinoma primary tumours. Using an in vivo model of metastatic progression, we further show that loss of LKB1 activates the early endoderm transcription factor SOX17 in metastases and a metastatic-like sub-population of cancer cells within primary tumours. The expression of SOX17 is necessary and sufficient to drive a second wave of epigenetic changes in LKB1-deficient cells that enhances metastatic ability. Overall, our study demonstrates how the downstream effects of an individual driver mutation can change throughout cancer development, with implications for stage-specific therapeutic resistance mechanisms and the gene regulatory underpinnings of metastatic evolution.

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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 [69]

    The Abstract and Discussion report that LKB1 loss drives epigenetic reprogramming in lung adenocarcinoma and enhances metastatic ability. The Discussion raises the plasticity of LKB1-deficient cells as a question for further study, rather than establishing that LKB1 loss facilitates lineage plasticity. (LLM, conf=0.83)

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Research works printed but not linked: 35

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Authors
Pierce, S. E., Granja, J. M., Corces, M. R., Brady, J. J., Tsai, M. K., Pierce, A. B., Tang, R., Chu, P., Feldser, D. M., Chang, H. Y., Bassik, M. C., Greenleaf, W. J., & Winslow, M. M.
Affiliations
  • Stanford Medicine (US)
  • University of Pennsylvania (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
  • Pierce, Sarah E.
  • Greenleaf, William J.
  • Winslow, Monte M.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2021-08
Volume
23
Issue
8
Pages
915-924
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-021-00728-4
PMC
PMC8355205
OpenAlex
W3191116136
Cited by
59
References
7
Citations by year
2026: 9 · 2025: 10 · 2024: 14 · 2023: 12 · 2022: 12 · 2021: 2
FWCI
3.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Cell Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health (5r01ca230919-05, AI057266, R01-CA230919, RM1-HG007735, HG007735)
  • National Human Genome Research Institute (RM1HG007735, UM1HG009436, P50HG007735, UM1HG009442)
  • National Cancer Institute (R01-CA230919, R01CA204620, R35CA209919, P30CA124435, T32CA009302)
  • National Institute of Allergy and Infectious Diseases (U19AI057266)
  • National Institute of Environmental Health Sciences (P30ES013508)
  • Stanford Cancer Institute (P30CA124435)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
LKB1, lung adenocarcinoma, metastasis, chromatin accessibility, epigenetic reprogramming, SOX17, tumor suppressor inactivation, metastatic progression, driver mutations, tumor evolution, treatment resistance
MeSH terms
Adenocarcinoma, Animals, Chromatin, Female, Humans, Lung Neoplasms, Male, Mutation, Neoplasm Metastasis, Protein Serine-Threonine Kinases, HMGB Proteins, Cell Line, Tumor, Mice, AMP-Activated Protein Kinases, SOXF Transcription Factors

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