LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
Abstract
LKB1is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation ofLkb1accelerates 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 fromLkb1deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enablesLkb1inactivation at tumor initiation and subsequentLkb1restoration in established tumors. Restoration ofLkb1in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis.Lkb1restoration 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 28, 2022
- Source ID
- 10.1038/s41467-022-28619-8
Entities
People
- Christopher W. Murray
- David B Shackelford
- David M Feldser
- Hongchen Cai
- Janos Demeter
- Jennifer J. Brady
- Min K Tsai
- Mingqi Han
- Monte M Winslow
- Peter K Jackson
- Ran Cheng
- Sarah E Pierce
Organizations
- National Cancer Institute
- National Institute of General Medical Sciences
- United States Department of Defense
- United States Department of Health and Human Services