GSE125408 YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in new targetable vulnerabilities in NF2-deficient tumor cells

Contributors : Shannon M White ; Chunling YiSeries Type : Expression profiling by arrayOrganism : Homo sapiensThe NF2 gene, which encodes the Merlin protein, is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2). Recent large-scale genome sequencing studies have also identified NF2 as one of the most frequently mutated genes in VHL-wild-type kidney cancers. Even though a wide array of downstream signaling pathways has been described for Merlin/NF2, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood. Using an inducible orthotopic kidney tumor model, we demonstrate for the first time that silencing of YAP/TAZ is sufficient to induce regression of pre-established NF2 deficient kidney tumors. Mechanistically, we show that YAP/TAZ ablation severely diminishes glycolysis by downregulating the transcription of several glycolytic enzymes and growth factors and RTK-PI3K-AKT signaling, resulting in growth arrest. On the other hand, YAP/TAZ depletion significantly increases mitochondrial respiration and overproduction of mitochondrial ROS, resulting in redox imbalance and oxidative stress cell death when challenged by nutrient stress. Furthermore, we identify lysosome-mediated cAMP-PKA/EPACdependent activation of the RAF-MEK-ERK pathway to be a novel resistance mechanism that allows NF2 deficient tumor cells to survive YAP/TAZ inhibition in vitro and in vivo. Finally, u...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by array Homo sapiens Source Type: research