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 profiling and the cells of origin. Previous work has shown that Lkb1 inactivation confers lung ADC with strong plasticity and makes them progressively transit to SCC in mice. This provides the first evidence to support the potential cell fate conversion implicated by the clinical observation of lung adenosquamous carcinoma (Ad-SCC), which contains mixed adenomatous and squamous pathologies with identical genetic alterations. However, the underlying mechanisms involving the transdifferentiation process remain unknown.

Recent work from the Chinese Academy of Sciences reveals that the transdifferentiation process is reliant on YAP, the major downstream effector of Hippo signal pathway, which functions as an essential barrier to squamous transdifferentiation, via regulation of ZEB2 and subsequent repression of DNp63. 

Under the supervision of Prof. JI Hongbin and Prof. ZHANG Lei from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Dr. GAO Yijun, ZHANG Wenjing and their colleagues have now reported YAP as a key player in the cell-fate conversion during lung ADC to SCC transdifferentiation. Studies of mouse model and human clinical specimens identify the pathology-specific expression and distribution pattern of YAP. Further functional study demonstrates that YAP acts as the essential barrier for squamous transdifferentiation through DNp63 repression via transcriptional regulation of ZEB2 expression.  

These findings shed light on the molecular basis for lung cancer phenotypic plasticity and provide important implications for YAP-targeted therapies in lung cancer. 

This work entitled “YAP inhibits squamous transdifferentiation of Lkb1-deficient lung adenocarcinoma through ZEB2-dependent DNp63 repression” was published online in Nature Communications on August 13, 2014. 

This project was supported by grants from the Ministry of Science and Technology of China, the Cross and Cooperation in Science and Technology Innovation Team program, the Strategic Priority Research Program of the CAS, the National Natural Science Foundation of China, the Postdoctoral FellowshipProgram of Shanghai Institutes for Biological Sciences, SA-SIBS Scholarship Program, China Postdoctoral Science Foundation. 

YAP acts as an essential barrier for this phenotypic conversion through ZEB2-mediated DNP63 repression. (Image by Prof. JI Hongbin’s group)