Hai Song’s and Li Shen’s laboratories cooperatively published a research article entitled “YAP drives fate conversion and chemoresistance of small cell lung cancer” in Science Advances on October 1th，2021, which reported that YAP regulates intratumoral heterogeneity and drug resistance of small cell lung cancer.
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is classified as a high-grade neuroendocrine (NE) tumor. SCLC is a particularly aggressive and deadly form of lung cancer characterized by fast growth, early metastasis and rapidly acquired therapeutic resistance. The standard chemotherapy for SCLC consists of platinum-based chemotherapy combined with the topoisomerase II inhibitor etoposide. A remarkable response to the chemotherapy is followed almost invariably by the development of resistant disease. However, the molecular mechanisms responsible for acquired therapeutic resistance in SCLC are largely unknown.
YAP is instrumental for tumor initiation and progression in multiple tissue types. In this study, we found activation of YAP can strongly suppress the neuroendocrine property of small cell lung cancer and elicit a fate change from NE to Non-NE. Induction of Rest is a critical step to suppress NE differentiation in SCLC. In-depth research showed that YAP promotes NE to Non-NE conversion through regulating Rest expression in Notch dependent and independent ways. They also found that Non-NE tumor cells are more resistant to chemotherapy drugs than NE tumor cells. Interestingly, Non-NE tumor cells undergo apoptosis after treatment with chemotherapy drugs, while chemotherapy drugs induce pyroptosis in NE SCLC cells. Further studies showed YAP activation in SCLC significantly inhibits the expression of GSDME, thereby inhibits the occurrence of pyroptosis and make small cell lung cancer more resistant to chemotherapy drug.
Figure1: YAP regulates the heterogeneity and drug resistance of small cell lung cancer
Dr. Qingzhe Wu, Jingxin Guo and Yuning Liu are the first authors. Dr. Hai Song and Li Shen are the corresponding authors.
