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

Christopher W. Murray, Jennifer J. Brady, Mingqi Han, Hongchen Cai, Min K. Tsai, Sarah E. Pierce, Ran Cheng, Janos Demeter, David M. Feldser, Peter K. Jackson, David B. Shackelford and Monte M. Winslow ()
Additional contact information
Christopher W. Murray: Stanford University School of Medicine
Jennifer J. Brady: Stanford University School of Medicine
Mingqi Han: University of California
Hongchen Cai: Stanford University School of Medicine
Min K. Tsai: Stanford University School of Medicine
Sarah E. Pierce: Stanford University School of Medicine
Ran Cheng: Stanford University School of Medicine
Janos Demeter: Stanford University School of Medicine
David M. Feldser: University of Pennsylvania
Peter K. Jackson: Stanford University School of Medicine
David B. Shackelford: University of California
Monte M. Winslow: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28619-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28619-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28619-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().