Metabolic Fitness and Plasticity in Cancer Progression

Metabolic adaptations are necessary for cancer cells to fuel their growth. Cancer cells with enhanced metabolic plasticity are better able to cope with the changing ATP and biosynthetic needs throughout tumor progression. Metabolic regulators such as hypoxia-inducible factor 1 (HIF-1), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and PPAR-gamma coactivator 1 alpha (PGC-1α) contribute to metabolic plasticity by sensing and reacting to nutrient availability and energy status. Metabolic plasticity can support therapeutic resistance by mobilizing mechanisms to overcome therapy-induced damages. Targeting metabolic flexibility using combinatorial therapies represents a promising avenue to improve patient outcome. Cancer cells have enhanced metabolic needs due to their rapid proliferation. Moreover, throughout their progression from tumor precursors to metastases, cancer cells face challenging physiological conditions, including hypoxia, low nutrient availability, and exposure to therapeutic drugs. The ability of cancer cells to tailor their metabolic activities to support their energy demand and biosynthetic needs throughout disease progression is key for their survival. Here, we review the metabolic adaptations of cancer cells, from primary tumors to therapy resistant cancers, and the mechanisms underpinning their metabolic plasticity. We also discuss the metabolic coupling that can develop between tumors and the tumor microenvironment. Finally, we consider potential metabolic interventions that could be used in combination with standard therapeutic approaches to improve clinical outcome. Cancer cells have enhanced metabolic needs due to their rapid proliferation. Moreover, throughout their progression from tumor precursors to metastases, cancer cells face challenging physiological conditions, including hypoxia, low nutrient availability, and exposure to therapeutic drugs. The ability of cancer cells to tailor their metabolic activities to support their energy demand and biosynthetic needs throughout disease progression is key for their survival. Here, we review the metabolic adaptations of cancer cells, from primary tumors to therapy resistant cancers, and the mechanisms underpinning their metabolic plasticity. We also discuss the metabolic coupling that can develop between tumors and the tumor microenvironment. Finally, we consider potential metabolic interventions that could be used in combination with standard therapeutic approaches to improve clinical outcome. a central nutrient sensor that senses an upwards shift in AMP:ATP ratio and inhibits the target or rapamycin complex I (TORC1). a process through which epithelial cells lose their cell polarity and adhesion and gain the properties of mesenchymal stem cells, which have elevated migratory and invasive capacity. amino acids that must be obtained through diet. the catabolic pathway through which glutamine is oxidized to incorporate the citric acid cycle. the metabolic pathway through which glucose is catabolized to pyruvate. a metabolic regulator that is stabilized under low-oxygen conditions and that has oncogenic properties. the process through which cells that underwent EMT revert back to an epithelial phenotype. the process by which cells may exchange nutrients and metabolic by-products with one another to sustain growth. the alignment of cell metabolism to the energetic needs and biosynthetic demands of the cell, as well as to the nutrient availability in the microenvironment. the ability of an organism to use different pathways to maintain metabolic fitness upon nutrient availability. For example, by switching ATP supply from OXPHOS to glycolysis in hypoxic conditions. the ability of an organism to adapt its metabolic program in order to maintain metabolic fitness across tumor states and environments. metabolic reaction or pathway that is critical for cell survival, which can be exploited for therapeutic intervention. a transcription factor that is often highly or constitutively expressed in cancer and which drives numerous metabolic pathways, including glutaminolysis and nucleotide synthesis pathways. the process by which oxygen is consumed to drive the production of ATP in the mitochondrial electron transport chain. a co-transcription factor and regulator of cellular metabolism. the reductive process through which glutamine-derived α-ketoglutarate is carboxylated to isocitrate and its isomer citrate via the NADPH-dependent isocitrate dehydrogenases (IDH1, IDH2), which is often coupled to de novo lipid biosynthesis. the ‘soil’ is the microenvironment in which metastatic cancer cells are the ‘seed’, and seeds grow best at peak metabolic fitness in a soil that contains the ideal composition of nutrients and supportive organisms. In imperfect conditions, the seed must adapt in order to survive and thrive. variations in the morphology and overall phenotype of cancer cells within a common tumor, some of which may favor tumor survival and progression.