Abstract
Simple SummaryMetabolic adaptation by cancer cells is enabled through the rewiring of metabolic processes, thereby allowing them to survive and thrive in diverse tissue microenvironments. It is also exploited to maintain cancer stemness, drive epithelial–mesenchymal transition, and gain therapy resistance. These critical cellular events are pertinent to the various steps of cancer progression. Mechanistic insights into nutrient addiction arising from such metabolic rewiring have revealed therapeutic vulnerabilities that can be exploited as novel treatment modalities or for drug development. This review discusses concepts and principles of metabolic plasticity and highlights current preclinical and clinical strategies aimed at targeting these metabolic derangements.Cancer metabolism is a hallmark of cancer. Metabolic plasticity defines the ability of cancer cells to reprogram a plethora of metabolic pathways to meet unique energetic needs during the various steps of disease progression. Cell state transitions are phenotypic adaptations which confer distinct advantages that help cancer cells overcome progression hurdles, that include tumor initiation, expansive growth, resistance to therapy, metastasis, colonization, and relapse. It is increasingly appreciated that cancer cells need to appropriately reprogram their cellular metabolism in a timely manner to support the changes associated with new phenotypic cell states. We discuss metabolic alterations that may be adopted by cancer cells in relation to the maintenance of cancer stemness, activation of the epithelial–mesenchymal transition program for facilitating metastasis, and the acquisition of drug resistance. While such metabolic plasticity is harnessed by cancer cells for survival, their dependence and addiction towards certain metabolic pathways also present therapeutic opportunities that may be exploited.
Highlights
IntroductionGlucose transporters and glycolytic enzymes are upregulated to utilize glucose for the synthesis of nucleotides, amino acids, and lipids
Glucose transporters and glycolytic enzymes are upregulated to utilize glucose for the synthesis of nucleotides, amino acids, and lipids. Alternate carbon sources such as glutamine, branched-chain amino acids, fatty acids, and lactate have been reported to fuel the growth of tumor cells, contribute towards cancer stemness or drive tumorigenesis [12]. Likewise, such metabolic reprogramming is seen in cell state transitions that contribute towards metastasis and confer drug resistance [13,14]
We explore how cancer metabolism is altered during events of cellular plasticity, mainly focusing on metabolic adaptations that are exploited by: (i) cancer stem cells (CSCs); (ii) cell state changes during epithelial–mesenchymal transition (EMT); and (iii) drug resistant cancer cells
Summary
Glucose transporters and glycolytic enzymes are upregulated to utilize glucose for the synthesis of nucleotides, amino acids, and lipids Alternate carbon sources such as glutamine, branched-chain amino acids, fatty acids, and lactate have been reported to fuel the growth of tumor cells, contribute towards cancer stemness or drive tumorigenesis [12]. Likewise, such metabolic reprogramming is seen in cell state transitions that contribute towards metastasis and confer drug resistance [13,14]. Insights into the roles that metabolic reprogramming plays in the adaptive nature of cancer cells may reveal new metabolic targets for drug development, or enable the redeployment of therapeutic options that can disrupt cancer cell metabolism in a specific and targeted manner
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