Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two major subtypes of non-small cell lung cancer (NSCLC) with distinct pathologies, biomarkers, gene expression profilings and the cells of origin. The mixed adenomatous and squamous pathologies with identical genetic mutations, however, has been consistently observed in a single lesion of human NSCLC, so called adenosquamous cell carcinoma (Ad-SCC), suggesting a monoclonality and the potential lineage transition between these subtypes. Whether there exists the dynamic lineage conversion between ADC and SCC in lung Ad-SCC remains as a fundamental yet unsolved question. 

Under the supervision of Prof. JI Hongbin from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, HAN Xiangkun, Dr. LI Fuming and their colleagues have now provided the first de novo evidences supporting the transdifferentiation of lung ADC to SCC in mice through the integrative studies of three animal models followed by molecular and pathological analyses. Further mechanistic studies show that the lysyl oxidase (LOX) mediated extracellular matrix remodeling tightly regulates this transdifferentiation process. Notably, the transition from ADC to SCC contributes to an acquisition of drug resistance upon the treatment of two different LOX inhibitors BAPN and DPA. This study represents as the first work in lung ADC to SCC transdifferentiation and paves the way for this emerging field. Considering that lung Ad-SCC presents as a more malignant subtype with poor prognosis among all subtypes of NSCLC, these findings might hold important implication for clinical lung cancer treatment. 

This study entitled “Transdifferentiation of Lung Adenocarcinoma in Mice with Lkb1 Deficiency to Squamous Cell Carcinoma” was published online in Nature Communications on Feb 17, 2014. 

The authors greatly thank Prof. LI Lin and Prof. ZHU Xueliang for helpful discussion and suggestion. This work was supported by the grants from the Chinese Academy of Sciences, the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Science and Technology Commission of Shanghai Municipality.  

A scheme showing the transdifferentiation process from lung adenocarcinoma to squamous cell carcinoma in Kras/Lkb1mice. (Image by JI Hongbin’s group)