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Nat Commun. 2014;5:3261. doi: 10.1038/ncomms4261.

Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma.

Author information

1
1] State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China [2].
2
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
3
1] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China [2] Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
4
Key Laboratory of Nutrition and Metabolism, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
5
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin 130022, China.
6
1] Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
7
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Abstract

Lineage transition in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of non-small cell lung cancer, as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma, remains a fundamental yet unsolved question. Here we provide in vivo evidence showing the transdifferentiation of lung cancer from ADC to SCC in mice: Lkb1-deficient lung ADC progressively transdifferentiates into SCC, via a pathologically mixed mAd-SCC intermediate. We find that reduction of lysyl oxidase (Lox) in Lkb1-deficient lung ADC decreases collagen disposition and triggers extracellular matrix remodelling and upregulates p63 expression, a SCC lineage survival oncogene. Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process. Notably, ADC and SCC show differential responses to Lox inhibition. Collectively, our findings demonstrate the de novo transdifferentiation of lung ADC to SCC in mice and provide mechanistic insight that may have important implications for lung cancer treatment.

PMID:
24531128
PMCID:
PMC3929783
DOI:
10.1038/ncomms4261
[Indexed for MEDLINE]
Free PMC Article

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