Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis

Abstract

The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.

The mitochondrial Ca2+ channel MCU is critical for tumor growth by supporting cell cycle progression and proliferation

“…These observations suggest that enhanced ER-to-mitochondria Ca 2+ transfer may be a feature associated with many types of cancer. Transformation also facilitated a rapid stimulation of respiration in response to an acute cytoplasmic Ca 2+ signal, which may be crucial for energy regulation to sustain increased bioenergetic demand during cancer progression ( Cardenas et al, 2010 ; Koval et al, 2019 ; Bustos et al, 2021 ; Herst et al, 2022 ).…”

Structural basis for transcription factor ZBTB7A recognition of DNA and effects of ZBTB7A somatic mutations that occur in human acute myeloid leukemia

“…The suggestion is that ZBTB7A has this effect via its transcriptional repression of genes for glycolytic enzymes. Metabolic reprogramming, in which glycolysis is elevated, is associated with a variety of cancers ( 50 , 51 , 52 ). ZBTB7A represses the transcription of several genes implicated in glycolysis ( SLC2A3 , PFKP , and PKM ) in several human cancer cells ( 9 ); whereas ZBTB7A knockdown in colon carcinoma cells HCT116 yielded increased glycolysis and proliferation ( 9 ); and loss of ZBTB7A sensitizes K562 cells to glycolysis inhibition ( 27 ).…”

PANK1 associates with cancer metabolism and immune infiltration in clear cell renal cell carcinoma: a retrospective prognostic study based on the TCGA database

“…Findings that metabolic demands change frequently during tumor initiation, progression, and metastasis have challenged our understanding of tumor biology and the development of novel therapeutics. Thus, investigating the role of TME cells in the remodeling of cancer cell energy metabolism has become an increasingly important area of research (38). Additionally, metabolic changes have been shown to occur in ccRCC.…”