Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment.
Shijie TangYun XueZhen QinZhaoyuan FangYihua SunChongzhe YuanYunjian PanYue ZhaoXinyuan TongJian ZhangHsinyi HuangYuting ChenLiang HuDasong HuangRuiqi WangWeiguo ZouYuan LiRoman K ThomasAndrea VenturaKwok-Kin WongHaiquan ChenLuonan ChenHongbin JiPublished in: National science review (2023)
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.
Keyphrases
- single cell
- transcription factor
- poor prognosis
- high grade
- rna seq
- low grade
- long non coding rna
- copy number
- stem cells
- dna binding
- machine learning
- genome wide identification
- climate change
- oxidative stress
- electronic health record
- artificial intelligence
- genome wide
- data analysis
- cancer therapy
- single molecule
- big data
- deep learning
- network analysis
- cell fate