Metabolic reprogramming is a key adaptive process in gastrointestinal (GI) cancers that extends beyond the Warburg effect to fuel tumor progression and therapy resistance. A critical nexus exists between this metabolic rewiring and tumor plasticity, where cancer cells gain stem-like properties and undergo epithelial-to-mesenchymal transition (EMT). This crosstalk is bidirectional: oncogenic signals drive metabolic changes, and resulting metabolites can epigenetically promote a plastic, aggressive phenotype. Consequently, this adaptability allows tumor subpopulations to survive conventional therapies by enhancing drug efflux, utilizing alternative nutrients, and entering quiescent states. The harsh tumor microenvironment further selects for these resilient, metabolically flexible cells, which are often responsible for relapse and metastasis. Current research is therefore focused on mapping the specific metabolic dependencies of these treatment-resistant cells. The ultimate goal is to identify novel therapeutic targets to disrupt this metabolic-plasticity axis, thereby sensitizing refractory GI tumors to existing treatments and improving patient survival.
This topic aims to explore the pivotal role of metabolic reprogramming in driving tumor plasticity and therapy resistance in gastrointestinal cancers. By dissecting this critical crosstalk, the Research Topic seeks to highlight novel mechanistic insights and emerging therapeutic vulnerabilities. This section aims to address the challenge of treatment resistance by illuminating underlying mechanistic links and facilitating the design of targeted interventions that prolong therapeutic efficacy and improve clinical prognoses.
• Molecular Mechanisms of Metabolic Plasticity: Investigations into the specific signaling pathways, oncogenic drivers, and epigenetic modifications that orchestrate metabolic adaptations in response to therapy and facilitate phenotypic switching (e.g., EMT, stemness).
• The Tumor Microenvironment (TME) as a Metabolic Niche: Analyses of the dynamic crosstalk between tumor cells and stromal components (e.g., cancer-associated fibroblasts, immune cells).
• Advanced Technologies for Metabolic Mapping: Applications of cutting-edge tools (e.g., single-cell metabolomics, spatial transcriptomics, stable isotope tracing) to decipher metabolic heterogeneity, identify rare resistant subpopulations, and map metabolic fluxes within tumors.
• Metabolic Vulnerabilities and Therapeutic Targeting: Preclinical and clinical studies exploring novel agents or dietary interventions that target critical metabolic dependencies (e.g., redox homeostasis, nucleotide synthesis, mitochondrial function) to re-sensitize resistant cancers to conventional therapies.
• Translational Biomarkers: Research focused on identifying metabolic biomarkers (from imaging, circulating metabolites, or tissue samples) for predicting treatment response and monitoring the emergence of resistance.
Keywords: Metabolic Reprogramming, Gastrointestinal Cancers, Tumor Plasticity, Therapy Resistance, Epigenetic Regulation
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