Abstract 4418: Enhanced endocytosis as a metabolic detour for cancer cells

Abstract

Abstract INTRODUCTION: Metabolic defects impair physiology and life cycle of every somatic cell. However, emerging evidence showed abnormalities in metabolic pathways paradoxically serve as initial steps in many types of human cancers. Little is known about the molecular mechanisms that confer metabolic adaptation and oncogenic predisposition for a transforming cell with intrinsic metabolic defect. In the present study, we explore the molecular mechanism that assists cellular adaptation when confronting metabolic deficiency, and its correlation acquisition of aggressive phenotypes. METHOD: We took advantage of clinical cases and in vitro cellular models with neomorphic IDH1 mutations, as a paradigm of metabolic deficiency-associated cancer. We investigated whole transcriptomic profiling based on RNA sequencing on IDH1-mutated cells and seek for selective activated canonical pathways. As a validation, we investigated the signature pathways in IDH1-mutated cells, with a focus on cytoskeleton assembly, cellular migration and endocytosis. Moreover, we investigated mTORC pathway and identified its pivotal role in the metabolic adaptation and cellular motility changes in IDH1-mutated cells. RESULTS: Transcriptomic profiling suggested profound activation in molecular pathways that govern cell movement, endocytosis, chemotaxis and invasion in IDH1-mutated cells. Hierarchical clustering analysis suggested that acquisition of R132C or R132H IDH1 mutant leads to consistent activation pattern for cellular movement. In addition, we confirmed that IDH1-mutated cells exhibit stronger capacity in cellular migration, endocytosis and cytoskeleton re-organization. Importantly, we demonstrated remarkable enhancement in endocytosis pathways in IDH1-mutated cells, suggesting cellular transformation eases metabolite uptake for metabolic deficient cell. Finally, we demonstrated that Rictor/mTORC2/Rac1 pathway is selectively activated in IDH1-mutated glioma cells, which is essential to enable cytoskeleton mobilization, endocytosis and acquisition of aggressive phenotype in transforming cells. CONCLUSION: Our findings demonstrate that metabolic deficiency leads to enhancement in food seeking behavior in cellular level, highlighted with enhanced cell motility, chemotaxis, and endocytosis; suggesting that this is an important molecular mechanism in cellular transformation during oncogenesis. This phenotypic transformation provides additional carbon sources, compensating for IDH mutation related alterations and may help explain the enhanced cell migration and invasion characteristic of these cancers. Citation Format: Yang Liu, Yanxin Lu, Aiguo Li, Orieta Celiku, Mark R. Gilbert, Chunzhang Yang. Enhanced endocytosis as a metabolic detour for cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4418. doi:10.1158/1538-7445.AM2017-4418