Editorial: Targeting cancer metabolic reprogramming for cancer therapy

Cancer cells utilize metabolic reprogramming to support metastasis, tumor growth, tumor immune suppression, and chemoresistance. While these dysfunctional signaling pathways and mechanisms remain to be fully elucidated, they may include organelle level involvement such as mitochondrial function, as well as the involvement of nutrients such as glutamine, lipids, or iron. While these mechanisms of tumor metabolic reprogramming are complex and can differ between heme-based and solid tumors, they do offer novel therapeutic targets for the development of new chemotherapeutics and immune-supportive agents. This Research Topic collected valuable contributions that explored the role of microRNA, mitochondrial metabolism and proteins, as well as lactic acid (Warburg) signaling in cancer tumor development and growth.

Shrestha et al. investigated the role of the microRNAs miR-143-3p and miR-506-3p on non-small lung cancer (NSCLC) proliferation and tumor growth. By combining in vitro and in vivo cancer models, they showed that the upregulation of both miR-143-3p and miR-506-3p led to a significant decrease in lung cancer cell proliferation and migration, along with a corresponding inhibition of tumor growth in mice. These findings indicated an exciting prospect of targeting these two microRNAs as a combinatorial treatment for NSCLC.

Additional studies on microRNA were done by Van den Bosch et al., which focused on the tumor-suppressive microRNA miR-7-5p as a novel therapeutic lead in tumor suppression. They developed and characterized a synthetic miR-7-5p mimic, named 5A2, which was tested in a panel of human cancer cell lines. They found that the formulation of 5A2 in a lipid nanoparticle INT-5A2 showed significant reduction of liver tumors in an experimental human liver tumor-bearing mouse model. Interestingly, 5A2 was shown to reduce key metabolic enzymes that support glycolysis and glutaminolysis, which led to a decrease in lactic acid secretion, a decrease in glycolysis, and a decrease in intracellular glutamate.

The role of lactate in tumor-associated macrophage (TAM) regulation and tumor progression was reviewed by Jin et al. There are important metabolic adaptations, which are characteristic of the solid tumors, that affect the immune response. This review focused on the role of lactic acid, a byproduct of aerobic glycolysis, and its role in TAMs in the tumor immune microenvironment. Lactic acid has been shown to modulate the TAM polarization by influencing the M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotype balance. The therapeutic potential of targeting the lactate metabolism is made possible by the ability to reprogram the TAMs for enhanced anti-cancer immunity, especially in solid tumors.

Lastly, a review by Zhu et al. focused on the role of mitochondrial ribosomal proteins (MRPs) in cancer. MRPs are crucial in translating protein encoded by the mitochondrial DNA and changes in their expression have been shown to be associated with significant remodeling of the tumor microenvironment. These changes include oxidative stress and reactive oxygen species changes, metabolic reprogramming, and mitophagy, which are implicated in cell proliferation and metastasis. Discussed MRPs examples include MRPL13 in breast cancer, MRPL12, MRPL13, MRPL15, and MRPL42 in lung cancer, MRPL43 in colorectal cancer, MRPL9 and MRPL14 in head and neck cancer, and MRPL49 and CRIF1 in acute myeloid leukemia. While these mitochondrial ribosomal proteins are important in the cellular signaling context, they also serve as novel prognostic biomarkers for precision oncology. The review also discussed the potential use of these MRPs in patient stratification during chemotherapy treatment and in clinical trials assessment of treatment impact.

The development of novel and effective cancer chemotherapeutics relies on identifying biologically relevant cellular targets, which is essential for managing the disease effectively. While it is generally understood that the metabolism of cancer cells is adapted for increased proliferation and niche adaptation, finding relevant drug targets remains a challenge. This collection of papers presented here highlights opportunities in the field of microRNA biology. As seen from the works discussed, these microRNAs may be effective drug targets as well as present novel biomarkers for cancer screening and assessing chemotherapeutic effectiveness. Additionally, the metabolism of immune cells within the cancer microenvironment may present a novel opportunity to move cold and hot tumors to be responsive to chemotherapeutics or even improve immunotherapies.

We hope that this Research Topic will serve as a valuable reference and inspire new findings on the mechanisms of metabolic reprogramming, the discovery of new targets, and the discovery and development of novel therapeutics and strategies that target metabolic dysregulation in cancer cells.

Author’s note

HVL is currently a program officer at the National Institute on Drug Abuse at the National Institutes of Health. The findings and conclusions presented in this article are those of the authors and do not necessarily reflect the views of the National Institute on Drug Abuse, the National Institutes of Health, or the U.S. Department of Health and Human Services.

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Footnotes

Edited and reviewed by: Ming Tan, China Medical University, Taiwan