A groundbreaking new study has unraveled the critical role of the one-carbon metabolic pathway as a defining molecular signature for CD44-positive intestinal-type gastric cancer—a discovery that could revolutionize targeted therapies and diagnostic precision in this aggressive cancer subtype. Forged by an international team led by Joo, S. and colleagues, and published in the prestigious journal Cell Death Discovery, this research elucidates the intricate biochemical landscape distinguishing CD44-expressing gastric tumors from their counterparts, paving the way for novel intervention strategies grounded in metabolic vulnerabilities.
Intestinal-type gastric cancer, a predominant histological variant of stomach malignancies, has long challenged oncologists due to its heterogeneous molecular profile and relatively poor prognosis. Among the known markers, the cell surface glycoprotein CD44 has garnered attention not only as a cancer stem cell marker but also due to its association with tumor aggressiveness, metastasis, and resistance to conventional therapies. Nonetheless, the metabolic underpinnings correlating with CD44 expression in this cancer subtype remained poorly defined until this landmark study offered compelling evidence implicating the one-carbon metabolic pathway as a cornerstone molecular feature.
The one-carbon metabolism cascade encompasses a series of enzymatic reactions crucial for nucleotide biosynthesis, methylation reactions, and redox homeostasis—metabolic processes fundamentally necessary for rapid cell proliferation and genomic fidelity. By integrating transcriptomic and metabolomic analyses, the researchers revealed that CD44-positive intestinal-type gastric cancers exhibit a robust upregulation of key enzymes involved in this pathway, including serine hydroxymethyltransferase (SHMT), methylenetetrahydrofolate dehydrogenase (MTHFD), and thymidylate synthase (TYMS). This enhanced metabolic flux suggests a tailored biochemical reprogramming facilitating the proliferative and survival advantage observed in these cancer cells.
Notably, the study utilized clinical tumor specimens alongside in vitro gastric cancer cell models to validate the observed molecular signatures. High-throughput gene expression profiling demonstrated a consistent correlation between CD44 positivity and elevated one-carbon metabolism gene expression networks. Metabolic flux assays further corroborated these findings, showing increased folate-mediated one-carbon unit transfer rates—a biochemical hallmark indicating an amplified anabolic state that supports nucleotide synthesis and epigenetic modifications critical for malignant transformation and progression.
The implications of this metabolic signature are profound. By harnessing advanced CRISPR-Cas9 gene editing and pharmacologic inhibition of select one-carbon enzymes, the authors experimentally diminished CD44-positive gastric cancer cell viability and tumorigenicity in xenograft mouse models. These manipulations led to cell cycle arrest, increased apoptosis, and compromised DNA repair mechanisms, underscoring one-carbon metabolism’s pivotal role in maintaining malignant phenotypes within this cancer subset. Such findings propel the one-carbon pathway as an attractive therapeutic target, championing a shift toward metabolism-centric precision oncology.
Further dissection of molecular interactions unveiled epigenetic modifications driven by methyl group donors generated through one-carbon flux as a potential mechanism reinforcing CD44 expression itself, suggesting a possible feedback loop sustaining stemness and oncogenicity. This bidirectional relationship between metabolism and gene regulation adds an additional layer of complexity to cancer biology, wherein metabolic circuits intertwine with transcriptional programs and epigenetic landscapes to dictate tumor behavior and heterogeneity.
Clinically, these discoveries bear significant promise for the development of diagnostic biomarkers. Liquid biopsy approaches detecting metabolic enzyme transcripts or circulating metabolites linked to the one-carbon pathway could serve as minimally invasive indicators predicting CD44 status and disease aggressiveness. Such advances would facilitate early identification of high-risk patients and real-time monitoring of therapeutic responses, advancing personalized medicine paradigms.
One-carbon metabolism inhibitors have previously been explored in other cancer contexts, yet this research provides the first compelling rationale to prioritize these agents specifically for CD44-positive intestinal-type gastric cancer. Drugs like methotrexate and pemetrexed, classical antifolates targeting this metabolic axis, might be repurposed or optimized to exploit the metabolic dependencies uncovered by Joo et al., potentially enhancing clinical outcomes in a patient population that often exhibits resistance to conventional chemotherapy.
The study’s comprehensive methodological approach—combining omics analyses, functional genomics, and preclinical models—offers an exemplary framework illustrating how dissecting cancer metabolism at the molecular circuitry level unravels novel vulnerabilities. This strategy not only deepens fundamental understanding but also charts a translational course for bringing laboratory insights to bedside application, accelerating the pipeline of innovative therapeutics.
Moreover, this research highlights the broader relevance of metabolic pathways in defining cancer subtypes beyond mere genetic mutations, advocating increased incorporation of metabolic phenotyping in future oncologic classification systems. Such integrative taxonomy would refine prognostic stratification and foster development of metabolism-informed therapeutic regimens tailored to specific tumor metabolic profiles.
While promising, the authors acknowledge limitations including the need for larger cohort validations and exploration of potential metabolic crosstalk with other tumor microenvironment components such as immune cells and stromal elements. Future investigations may also examine resistance mechanisms arising from metabolic plasticity and compensatory pathways, as well as combinatorial strategies integrating metabolic inhibitors with immunotherapy or targeted agents.
This discovery of the one-carbon metabolic pathway as a molecular hallmark of CD44-positive intestinal-type gastric cancer opens an exciting frontier. By illuminating how altered metabolism intertwines with cellular phenotypes fundamental to cancer aggressiveness, this work sets the stage for innovative therapeutic designs centered on disrupting cancer cell metabolic networks. It represents a crucial step towards metabolic precision oncology tailored to the molecular identities of gastric tumor subtypes.
With gastric cancer representing a significant global health burden and survival rates stagnating, breakthroughs such as these offer hope of translating molecular understanding into meaningful clinical benefit. As research continues to elucidate metabolism’s multifaceted roles in tumor biology, integrating such insights promises to transform gastric cancer management through targeted interventions exploiting tumor-specific metabolic dependencies.
In summary, the identification of the one-carbon metabolic pathway as a novel molecular signature for CD44-expressing intestinal-type gastric cancer reframes our understanding of tumor biology and revitalizes metabolic targeting as a cornerstone of future therapeutic strategies. The study by Joo and colleagues is not merely a significant academic advance but a clarion call to the cancer research community to harness metabolism in the ongoing quest to ameliorate lethal malignancies through science-driven precision medicine.
Subject of Research: Molecular and metabolic characterization of CD44-positive intestinal-type gastric cancer with emphasis on the one-carbon metabolic pathway.
Article Title: One-carbon metabolic pathway is a novel molecular signature for CD44-positive intestinal-type gastric cancer.
Article References:
Joo, S., Bae, Y., Yoon, B.K. et al. One-carbon metabolic pathway is a novel molecular signature for CD44-positive intestinal-type gastric cancer. Cell Death Discov. 11, 399 (2025). https://doi.org/10.1038/s41420-025-02704-5
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