Regulatory Networks in Cancer Cell Metabolism

Metabolism is a broad research area with involvement in physiologic and pathologic conditions. Metabolic reprogramming is a hallmark of cancer as it allows cancer cells to support anabolic growth and evade programmed cell death mechanisms. Alterations in cellular transcriptional profiles, signaling cascades, and protein-protein interaction networks confer selective advantages to cancer cells in the tumor-immune microenvironment while potentially introducing metabolic vulnerabilities that can be exploited for cancer therapy. Moreover, alterations in anabolic and catabolic processes have been shown to play a key role in the activation, self-renewal, and differentiation of cancer stem cells. In this context, mitophagy, the mechanism by which damaged or dysfunctional mitochondria are selectively removed through autophagy, has been shown to be intricately associated with the occurrence of metastasis and with the metabolic rewiring of cancer stem cells.

Chemotherapies targeting metabolism have been largely used in clinics for decades, indicating the effectiveness of these therapeutic approaches. However, anticancer drugs targeting general proliferative metabolism also target rapidly proliferating non-malignant cells, causing a series of severe side effects. Moreover, many cancers display de novo or acquired resistance to antimetabolite drugs. Thus, greater knowledge and understanding of the main players and mechanisms involved in cancer-dependent metabolic reprogramming can inform the development of new precision therapeutic approaches. For instance, several drugs modulating autophagy are currently in clinical trials in multiple cancer types, and a greater understanding of metabolic processes in the tumor microenvironment is crucial to understand T cell exhaustion, which is extremely relevant to both checkpoint blockade and CAR-T therapy.

In this Research Topic, we aim to highlight recent advances in describing and understanding the regulatory networks in cellular metabolism in cancer and how they can be targeted in precision medicine. We welcome the submission of Original Research and Review articles on the following topics:

• Modulation of regulatory proteins in the autophagy/lysosomal pathways and their crosstalk with other pathways (e.g. cell proliferation)

• Transcriptional alterations associated with deregulated anabolic and catabolic pathways

• Modulation of protein-protein interaction networks in cellular metabolism through computational, genome-wide, or large-scale experimental approaches

• Metabolic alterations that confer a selective advantage to cancer cells in the tumor-immune microenvironment

• Metabolic programs that are key to the functionality of immune cells involved in anti-tumor immunity

• Targeting metabolic processes in cancer therapy

Dr. Pier Federico Gherardini holds stock in HepaTx and Teiko.bio. and Dr. Gennaro Napolitano receives funding from Orphazyme. All other editors declare no conflicts of interest.