Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment Journal Article
| Authors: | Tang, S.; Xue, Y.; Qin, Z.; Fang, Z.; Sun, Y.; Yuan, C.; Pan, Y.; Zhao, Y.; Tong, X.; Zhang, J.; Huang, H.; Chen, Y.; Hu, L.; Huang, D.; Wang, R.; Zou, W.; Li, Y.; Thomas, R. K.; Ventura, A.; Wong, K. K.; Chen, H.; Chen, L.; Ji, H. |
| Article Title: | Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment |
| 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. |
| Keywords: | adenocarcinoma; adenosquamous carcinoma; egfr; cell carcinoma; mouse model; clinicopathological features; acquired-resistance; driver mutations; lsd1; cancer; alk fusion; alk rearrangement; luas; counteracting tf regulatory network; cxcl3; cxcl5 |
| Journal Title: | National Science Review |
| Volume: | 10 |
| Issue: | 4 |
| ISSN: | 2095-5138 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-04-01 |
| Start Page: | nwad028 |
| Language: | English |
| ACCESSION: | WOS:000965344500001 |
| DOI: | 10.1093/nsr/nwad028 |
| PROVIDER: | wos |
| PMCID: | PMC10084920 |
| PUBMED: | 37051524 |
| Notes: | Article -- nwad028 -- Source: Wos |
