Abstract A38: A 4-gene YAP-related pathway expression signature informs about dependence of tumors on Hippo pathway signaling
Authors: Mazur Johanna , Kreis Julian , Trivier Elisabeth , Dillon Christian , Wienke Dirk , Staub Eike 
Published: September 2020

Abstract
The Hippo pathway is not only important for control of organ size in animals, it has also emerged as an important regulator of cancer development and progression. A robust surrogate for pathway activity is of importance to characterize the role of this pathway within primary tumors or for distinct tumor models. Gene expression signatures have been frequently used as downstream integrators for pathway activity. To enable assessment of Hippo pathway activity in transcriptomic profiles of cancer patients and models, we developed a protocol to distill a multigene expression signature from gene expression data and gene dependency screens in cell lines. Based on Achilles and DRIVE shRNA data together with expression data from the CCLE cell line panel, we first developed a 16-gene signature that reflects association with YAP1/TEAD1 dependency and coexpression with YAP1. To focus only on direct targets of YAP/TAZ, we took the intersection of our 16-gene signature and the 22-gene YAP/TAZ target score by Wang et al., Cell Reports 2018. The resulting gene signature consists of the four genes AMOTL2, CRIM1, CYR61, and MYOF. We tested the robustness of this 4-gene Hippo signature on gene expression data from The Cancer Genome Atlas (TCGA). We found that the 4-gene Hippo signature delivers high coherence scores in nearly all cancer types of the TCGA cohort. For these indications, our analysis suggests that the 4 genes constitute a coherently regulated expression module that warrants further investigation. We developed a summary signature Hippo score to stratify patients or samples according to their pathway activity and compared this score with others from a collection of more than 250 gene expression signatures. We observed that the Hippo signature score is often highly correlated with several published signatures that inform epithelial mesenchymal transition or cancer cell stemness. A cohort enrichment analysis on the TCGA data identified those indications, where most of the patients of this cohort have high signature scores and where YAP/TAZ activity could be an oncogenic driver. To refine this set of indications further, we performed a survival analysis (both overall and progression-free). We selected only those indications where the prognosis for patients with high signature score is worse compared to patients with low signature score. This analysis revealed that in mesothelioma (MESO), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), and brain lower-grade glioma (LGG), the Hippo pathway could be an oncogenic driver and may represent a promising target for future therapies. Our findings can support drug development by suggesting preclinical models (cell lines, PDX models), cancer indications, and even patients within indications by using our 4-gene signature as a predictive biomarker for oncogenic YAP/TAZ activity.
Citation Format: Johanna Mazur, Julian Kreis, Elisabeth Trivier, Christian Dillon, Dirk Wienke, Eike Staub. A 4-gene YAP-related pathway expression signature informs about dependence of tumors on Hippo pathway signaling [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A38.