One-carbon metabolism links tissues in cancer cachexia wasting
Multi-omics profiling across eight tissues in cachectic mice points to one-carbon metabolism as a shared pathway tied to muscle wasting, inflammation and glucose use.
Zusammenfassung
Cancer cachexia is a wasting syndrome that nutrition alone cannot reverse, and its metabolic drivers are poorly understood. Researchers profiled metabolites, gene expression and 13C-glucose tracing across tumours and multiple host tissues in the C26 colon-cancer mouse model. They compared healthy controls, mice with a non-cachexia-inducing tumour, pre-cachectic mice and cachectic mice. One-carbon metabolism emerged as a pathway altered across cachexia-targeted tissues. In muscle it was linked to inflammation, glucose hypermetabolism and atrophy. The same rewiring appeared in five other mouse models (Panc02, 8025, ApcMin, LLC, KPP), in a humanised cachexia mouse model, and in patients with cancer and muscle wasting. The work is a resource for understanding tumour–host metabolic crosstalk and suggests a candidate pathway for future biomarker and intervention research. It is preclinical, and the main model used male mice.
Detaillierte Zusammenfassung
Cachexia affects most patients with advanced cancer and is among the strongest predictors of mortality. It causes involuntary loss of weight and muscle, functional decline and poorer treatment tolerance. Reduced appetite is only part of the picture. By definition, cachexia cannot be fully reversed by conventional nutritional support, which implies maladaptive metabolic reprogramming between tumour and host. Most earlier metabolomic studies examined only blood or muscle, so a multi-organ view of how metabolism changes as wasting progresses has been missing.
The authors built a spatio-temporal metabolic atlas in the well-established C26 colon-carcinoma mouse model. They compared four groups: PBS-injected healthy controls, mice with a non-cachexia-inducing NC26 tumour, pre-cachectic C26 mice (before weight loss), and cachectic C26 mice (about 10% average weight loss). After a 6-hour fast, animals received an intraperitoneal injection of uniformly labelled [13C6]-glucose. One hour later the team collected the tumour and host tissues, including plasma, liver, epididymal and inguinal white fat, heart, and gastrocnemius and soleus muscles. They integrated metabolomics, RNA sequencing and isotope tracing. Only cachectic C26 mice lost significant body weight, fat mass and lean mass, and tumour size was comparable across tumour groups. This means the metabolic differences are not simply due to tumour burden.
The central finding is that one-carbon metabolism is a tissue-overarching pathway dysregulated in cachexia-targeted organs, in both mice and patients with metabolic wasting. In skeletal muscle, this rewiring was linked to inflammation, glucose hypermetabolism (shown through the 13C-glucose tracing) and atrophy, including in cultured myotubes. The multi-omics data also pointed to regulatory nodes that were controlled by systemic inflammation. The same metabolic changes were found in five additional mouse models (Panc02, 8025, ApcMin, LLC and KPP) and in a humanised cachexia mouse model. This suggests the pathway is not specific to a single tumour type or cell line.
The work is a resource and a framework rather than a treatment. One-carbon metabolism supports nucleotide synthesis, methylation and redox balance. Its coordination across tissues suggests that cachexia involves an organism-wide metabolic programme and not isolated organ damage. The findings may inform circulating-metabolite biomarkers for identifying patients at risk of wasting, and may identify targets for future interventional studies. Cross-species support from patient samples strengthens the translational case.
Several caveats apply. The primary data come from male mice and a subcutaneous C26 model, which cannot fully capture human cancer cachexia, including sex differences, age, prior therapies and comorbidities. The tracer data are a one-hour snapshot after a single glucose bolus in fasted animals. The evidence is associative: this summary does not show that targeting one-carbon metabolism prevents wasting. Details of the patient cohort and any functional interventions were not available in the portion of the paper reviewed, so these findings should be seen as hypothesis-generating.
Wichtigste Erkenntnisse
- Integrated metabolomics, RNA-seq and 13C-glucose tracing across tumour and seven host tissues mapped metabolic changes from pre-cachexia to cachexia in C26 mice.
- One-carbon metabolism was altered across cachexia-targeted tissues, linking organs in a shared metabolic response to cancer.
- In muscle, one-carbon pathway changes were tied to inflammation, glucose hypermetabolism and atrophy, including in myotubes.
- The same rewiring appeared in Panc02, 8025, ApcMin, LLC and KPP models, plus a humanised cachexia mouse model.
- Findings were supported by observations in patients with cancer and muscle wasting, suggesting translational relevance.
Methodik
Male C26 tumour-bearing mice were studied at pre-cachectic and cachectic stages, alongside PBS controls and non-cachexia-inducing NC26 tumour controls. After a 6-hour fast and an intraperitoneal [13C6]-glucose injection, tumour and tissues (plasma, liver, fat depots, heart, skeletal muscles) were collected after 1 hour for metabolomics, RNA sequencing and tracer analysis. Findings were then tested in five other mouse models, a humanised model and patient data.
Studienlimitierungen
The main dataset comes from male mice with a single subcutaneous tumour model, and the tracing reflects a short post-bolus snapshot, which limits generalisability to human disease. The findings are largely correlative, so whether modulating one-carbon metabolism changes wasting outcomes is untested here. This summary is based on the abstract, introduction and early results available, so details on patient cohort size and validation experiments are not covered.
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