Mitochondrial Metabolism: Yin and Yang for Tumor Progression

Abstract

Altered metabolism is a distinct feature of cancer cells. During transformation, the entire metabolic network is rewired to efficiently convert nutrients to biosynthetic precursors to sustain cancer cell growth and proliferation. Whilst the molecular underpinnings of this metabolic reprogramming have been described, its role in tumor progression is still under investigation. Importantly, the mitochondrion is a central actor in many of the metabolic processes that are altered in tumors. Yet, we have only begun to understand the dualities of mitochondrial function during cancer metastasis and therapy resistance. Paradoxically, mitochondrial metabolism can be both advantageous and detrimental to these processes, highlighting the need for a better understanding of the molecular and microenvironmental cues that define the role of this fascinating organelle. In this review article, we present an updated view on the different mitochondrial metabolic strategies adopted by cancer cells to overcome the many hurdles faced during tumor progression.

Figure 1. Metabolic adaptations during cancer progression.

Schematic representation of the evolution and progression of cancer, based on specific metabolic rewiring. Upon the establishment of an initial tumor mass, the acquisition of additional genetic mutations can lead to metabolic changes that will confer cancer cells different proliferative/survival capabilities. Survival of cancer cells and subsequent tumor progression is dependent on the acquisition of a successful metabolic state, defined here as metabolic flexibility. Please note that genetic mutations have been depicted as single consecutive events for simplicity, but various cumulative mutations can occur at each stage.

Figure 2. Metabolic modulation during metastatic dissemination.

Schematic representation of the stages of metastatic dissemination (proliferation, dissemination and metastasis). Right panel provides a summary of the metabolic adaptation exhibited by different tumor types and the estimated exposure to reactive oxygen species (ROS). *, glycolytic activity is presumed from results indicating reduced mitochondrial mass **, glycolytic activity is presumed from the progressive decrease in mitochondrial oxidative transcriptional programs from primary to metastatic cells. References: 1- Piskounova E. et al., Nature 2015; 2- Torrano V. et al., Nature Cell Biology 2016; 3- Le Bleu V.S. et al., Nature Cell Biology 2014; 4- Dupuy F. et al., Cell Metabolism 2015). Met: Metastasis.

Figure 3. Metabolic modulation as a phenomenon underpinning therapy resistance.

Schematic representation of how metabolic adaptations can enable resistance to anticancer therapies. The acquisition of drug resistance induces new metabolic essentialities that can be harnessed to specifically target resistant cells.