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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation
Shijie Tang1, Yun Xue1,2, Zhen Qin1
1State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
Abstract:
Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors (TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.
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