Abstract A39: The role of YAP in regulating glycogen metabolism in pancreatic cancer

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is driven largely by oncogenic KRAS mutations, making KRAS and its downstream effectors, in theory, ideal candidates for therapeutic intervention. Unfortunately, attempts to directly inhibit KRAS or its effectors have either been unsuccessful or ineffective and, as a result, there is much interest in identifying novel downstream effectors of oncogenic KRAS signaling. Yes-associated protein (YAP) has been shown to be an essential mediator of oncogenic KRAS signaling during PDAC progression as well as a marker for poor prognosis in PDAC patients. YAP is required for tumor recurrence and is able to compensate for loss of oncogenic KRAS in several cancer types, suggesting interplay between these pathways. YAP is a transcriptional co-activator that partners with transcription factors to control organ size, and upregulation of YAP is frequently observed in human cancers. Downstream target genes of YAP include cyclins and growth factors involved in proliferation, but YAP also induces stem cell properties, drug resistance, and metastasis, suggesting the presence of additional targets that affect various cellular processes. As KRAS is a major regulator of cellular metabolism and can upregulate scavenging pathways, such as autophagy and macropinocytosis, we hypothesize that YAP may also play a role in metabolic reprogramming of pancreatic cancers based on its importance in tumor initiation and progression. Our data demonstrate that YAP depletion in PDAC cells leads to dysregulated glycogen metabolism through regulation of uridine diphosphate glucose (UDP-Glc), the direct glucosyl donor for glycogen synthesis. UDP-Glc is synthesized from glucose-1-phosphate and uridine triphosphate (UTP) by UDP-Glc pyrophorphorylase 2 (UGP2), the sole enzyme responsible for this reaction in mammalian cells. YAP-depleted cells showed corresponding decrease of UGP2 mRNA and protein levels in a panel of PDAC cell lines. TCGA provisional dataset analysis showed a statistically significant tendency towards co-occurrence (p<0.001) between YAP and UGP2 mRNA levels in PDAC patients, and immunohistochemistry of tissues samples showed high correlation between YAP and UGP2 expression patterns, suggesting this regulation also exists in PDAC patients. Cells depleted of UGP2 showed a marked decrease of cell growth in 2D and 3D cultures, suggesting that UGP2 plays an important role in PDAC cell survival and proliferation. Interestingly, cells expressing oncogenic KRAS or its direct downstream effector, BRAF, have increased UGP2 expression and glycogen levels that are YAP-dependent. This suggests that glycogen metabolism may be an integral part of YAP-dependent KRAS signaling and that this pathway has an important function in PDAC cells. This is a novel role of YAP that has not been previously reported, and here we seek to understand the mechanism of how YAP regulates this pathway and its function in PDAC cells. Citation Format: Sung Eun (Monica) Kim, Jacqueline Galeas, Frank McCormick. The role of YAP in regulating glycogen metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr A39.