Abstract A30: Two faces of YAP: Oncogene in malignant progression but barrier for phenotypic transition in LKB1-deficient lung cancer

Abstract

Abstract Hippo signaling is actively involved in adult tissue homeostasis and cell fate determination. Previous studies have linked the activation of YAP (the major downstream effector of Hippo pathway) with LKB1 deficiency. Here, we characterize the function of YAP in the malignant progression and phenotypic plasticity of LKB1-deficient lung tumors. Using various lung cancer mouse models, we show that YAP expression significantly accelerates lung adenocarcinoma (ADC) malignant progression in KrasG12D mice whereas YAP deletion dramatically delays the process in Lkb1L/L/KrasG12D mice, suggesting that YAP functions as an essential mediator of malignant progression of Lkb1-deficient lung ADC. Further mechanistic studies identified Survivin as the mediator downstream of YAP in promoting malignant progression of Lkb1-deficient lung ADC. Knockdown of Survivin mimics the inhibitory phenotype of YAP knockdown whereas ectopic expression of Survivin rescues the inhibitory function of YAP knockdown. Our previous work has shown LKB1 inactivation confers lung ADC with strong plasticity to progressively change the cell fate and transit to squamous cell carcinoma (SCC). We find that ectopic YAP expression dramatically inhibits ADC to SCC transdifferentiation whereas knockdown of YAP conversely accelerates the transition process. YAP is initially activated by LKB1 loss in ADC, leading to ZEB2 up-regulation in ADC cells, which binds to DNp63 gene promoter to repress DNp63 transcription. During the transition process, extracellular matrix (ECM) depletion in ADC inactivates YAP, thus relieves ZEB2 mediated default repression on DNp63 transcription in ADC, leading to the initiation of squamous differentiation program. Together, these findings uncover the two faces of YAP in lung tumor malignant progression and phenotypic plasticity. YAP is an essential mediator of malignant progression of Lkb1-deficient lung ADC via regulating Survivin whereas an important barrier for lung cancer transdifferentiation through ZEB2 dependent DNp63 repression. Those works shed light on the fundamental role of YAP in regulating cancer progression and lineage phenotypic transition in LKB1 deficient lung tumors, which might help future development of better therapeutic strategies. Citation Format: Wenjing Zhang, Yijun Gao, Xiangkun Han, Fuming Li, Hongbin Ji. Two faces of YAP: Oncogene in malignant progression but barrier for phenotypic transition in LKB1-deficient lung cancer. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A30.