2019.11.22 Hybrid metabolic phenotype and mitochondria-nuclear crosstalk can regulate breast cancer progression
题 目： Hybrid metabolic phenotype and mitochondria-nuclear crosstalk can regulate breast cancer progression.
报告人：Dr. Benny Abraham Kaipparettu,
Associate Professor, Department of Molecular and Human Genetics，Baylor College of Medicine, Houston, TX, USA
Abnormal metabolism is a hallmark of cancer. Mitochondria are semiautonomous organelles within cells that play an important role in cellular energy metabolism, free radical generation, and apoptosis. Mitochondria contain their own genome (mtDNA), which encodes a number of proteins critical for energy metabolism, particularly in oxidative phosphorylation (OXPHOS). They are also the major source of generating reactive oxygen species (ROS). In a traditional view, cancer cells largely utilize glycolysis for energy production irrespective of the presence of oxygen. Recently, increasing experimental evidence shows a critical role of OXPHOS in tumorigenesis and metastasis. However, how cancer cells orchestrate glycolysis and OXPHOS to facilitate malignancy is largely unknown. We used mathematical model focusing on a core metabolism regulatory circuit, composed of 5' AMP-activated protein kinase (AMPK), a master regulator of OXPHOS, hypoxia-inducible factor 1 (HIF-1), a master regulator of glycolysis and reactive oxygen species (ROS), a key modulator of AMPK and HIF-1 activities. Using our models, we proposed a hybrid metabolic phenotype in which cancer cells can effectively use both glycolysis and OXPHOS. Moreover, using different transmitochondrial cybrid models, we analyzed the mitochondria-nuclear crosstalk and mitochondrial retrograde regulation in metastatic progression. Our computational modeling as well as the in vitro and in vivo experimental approaches suggests that the metastatic cancer cells effectively use alternative energy resources in addition to the glucose pathway to maintain their active hybrid phenotype. Moreover, mitochondrial energy reprogramming is critical in the regulation of important oncopathways in aggressively metastatic cells.
Dr. Kaipparettu is an Associate Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, USA. His research team focuses on the role of mitochondrial metabolism and mitochondria-nuclear crosstalk in cancer. They have proposed that many aggressive cancer models maintain a hybrid metabolic phenotype (a combination of glycolysis and active oxidative phosphorylation) that can provide the plasticity for tumor cells to proliferate and metastasize. Moreover, his group has shown that metabolic reprogramming is important in the activation of critical oncopathways and therapeutic response of tumors.