Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.

Xiaolei Li,Silvia Ribback,Marcella Sini,Lijie Jiang,Julien Calderaro,Xin Chen,Junyan Tao,Frank Dombrowski,Daniel Azoulay,Diego F Calvisi,Antonio Cigliano,Maria I Demartis,Kirsten Utpatel,Katja Evert,Chunmei Wang,Yan Liu,Matthias Evert

doi:10.18632/oncotarget.3546

Abstract

Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.

Highlights

Primary liver cancer is one of the most common malignancies in adults and a leading cause of cancer related deaths worldwide [1]
At the histological level, ~80% of the liver parenchyma from PIK3CA/Yes-associated protein (Yap) mice was occupied by tumor lesions, with the remaining liver tissue consisting of lipid-rich hepatocytes and normal liver tissue (Figure 1C-H)
Three distinct tumor types were detected in PIK3CA/Yap mice: (i) pure hepatocellular (~40% of all detected tumors), characterized by a solid or macrotrabecular growth pattern, often accompanied by cytoplasmic lipid accumulation and mild cytological atypia; (ii) pure cholangiocellular (~10%), forming primitive ducts and exhibiting stromal reaction; (iii) mixed Hepatocellular carcinoma (HCC)/CCC (~50% of the tumor lesions), with a hepatocellular component and the other component consisting of spindle-like or oval-cell-like small basophilic cells that resembled CCA-cells (Figure 1C-H)

Summary

Introduction

Primary liver cancer is one of the most common malignancies in adults and a leading cause of cancer related deaths worldwide [1]. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the major www.impactjournals.com/oncotarget types of primary liver cancer, accounting for almost 90% and ~10% of all liver tumors, respectively [2]. Another liver tumor entity, known as mixed HCC/CCA, can occur, at significantly lower frequency [3]. Due to its increasing incidence and related poor survival [1], innovative therapeutic options for liver cancer patients are necessary. For this purpose, a deeper knowledge of the molecular mechanisms underlying liver cancer development is highly required. In HCC, Yap has been identified as a driver oncogene [8] and an independent factor in predicting poor disease-free and overall survival [9]

Methods

Results

Conclusion