Role of Metabolic Reprogramming in Tumor Adaptation to Anti-angiogenic Therapy

AbstractAnti-angiogenic agents currently used in clinic target the vascular endothelial growth factor (VEGF) signaling pathway via an anti-VEGF antibody (bevacizumab,Avastin®) or small-molecule receptor tyrosine kinase inhibitors (RTKIs). Among theseinhibitors, sunitinib (SUTENT®, Pfizer) and sorafenib (Nexavar®, Bayer and Onyx),two multi-RTKI also provides clinical benefit to patients with renal cell carcinoma oradvanced gastrointestinal stromal tumors (GISTs). While these drugs were expected toincrease the overall survival or progression-free survival of patients, the survivalbenefits of anti-angiogenic drugs have been relatively modest. Alarmingly, preclinicalstudies have reported increased tumor growth and metastatic formation after thewithdrawal of treatment with VEGF receptor inhibitors. However, the mechanismsgoverning resistance that occur both in tumor cells and in the tumor microenvironmentare still poorly understood. Fundamentally, cancer cells differ from normal cellsregarding how their metabolic pathways are used to fuel cellular growth and survival.Throughout this work, we aim at understanding and evaluating the processes leadingto tumor adaptation to angiogenesis inhibitors.In this work, we have used a model of human MDA-MB-231 and HT-29xenografts, tumors shrank and metastases were inhibited, whereas treatmentwithdrawal accelerated tumor regrowth and metastatic dissemination to differentorgans. Similar effects were observed with a transgenic model of MMTV-PyMT miceand syngeneic mouse models of 4T1 and LLC tumors. Multidisciplinary approachesincluding transcriptomics, proteomics, metabolomics through Nuclear MagneticResonance spectroscopy (NMR), as well as histochemical and biochemical analysesrevealed a shift toward glycolytic phenotype during TKI treatment and lipidmetabolism and increased TCA activity after TKI treatment withdrawal, which isassociated with rapid tumor regrowth and accelerated metastatic dissemination. Wealso demonstrated the functional implications of lipogenesis and fatty acid synthase(FASN) in this process by the blockade of tumor relapse through pharmacologicalinhibition and downregulation of FASN with orlistat and shRNA, respectively.In order to elucidate the nature of lipids deposited in tumors after treatmentwithdrawal, we implemented a method for the identification and the localization ofspecific low-abundant isobaric lipids in cancer xenografts by FTICR MALDI imagingcoupled with electrospray mass spectrometry (LC-ESI-MS).Overall, by providing a detailed metabolic profile of tumor adaptationduring and after RTKI treatment, our study sheds light on recent alarmingclinical data reporting that RTKI treatment break could boost cancermalignancy.