Abstract BS3-1: Dominance of mitochondria in determining the malignant phenotype

Abstract

Abstract 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. They are also the major source of generating reactive oxygen species (ROS) in the cell. Advances in cancer metabolism research over the last decade have enhanced and modified our understanding on Warburg effect. It is now known that mitochondria in tumors are not always defective in their ability to carry out oxidative phosphorylation. Instead, in proliferating cells, mitochondrial energy pathways are reprogrammed to meet the challenges of macromolecular synthesis and to escape from apoptosis. Mitochondrial retrograde regulation (MRR) is a bidirectional communication between mitochondria and nucleus. MRR is triggered by mitochondrial functional demands and it responds in a continuous manner to the changing metabolic needs of the cell. At present, it is not clear whether mitochondrial genomic status or metabolomic reprogramming affect nuclear genome stability. Also, limited evidence is available on the significance of proteins involved in the inter-genomic cross talk in the regulation of tumorigenesis. Transmitochondrial cybrids (cybrids) are a great utility for the study of the functional effects of mitochondria in a defined nuclear background. Cybrids are constructed by fusing enucleated cells harboring mitochondria of interest with ρ0 cells (mtDNA-depleted cells). Our approach of discovering mitochondria regulated pathways using cybrid models and their in vitro and in vivo validation in different breast cancer cell lines and patient derived xenograft models suggest that mitochondrial metabolic character and retrograde signaling are playing important roles in oncogenic transformation and metastasis. Importantly, mitochondria-nuclear crosstalk is critical in the regulation of some of the major cancer pathways. Compared to hormone regulated/responsive breast cancers, triple negative breast cancer patients suffer from worse overall survival, significantly shorter disease-free and post-recurrence survival. Due to the lack of known oncogenic drivers for triple negative breast cancer, clinical benefit from currently available targeted therapies is limited, and new therapeutic strategies are urgently needed. Thus, understanding MRR and mitochondria mediated oncogenic signature is critical in understanding the currently limited known etiology and treatment resistance of certain subgroups of cancers like the triple negative breast cancer. Citation Format: Kaipparettu BA. Dominance of mitochondria in determining the malignant phenotype. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr BS3-1.