Abstract
Objectives
Current studies have confirmed that the sensitivity of the ketogenic diet (KD) therapy for cancer depends on the low expression of ketolytic enzymes. However, increasing evidence showed that heterogeneity of tumor metabolism leads to inconsistent efficacies of KD therapy, which broke the illusion of the possibility of cancer treatment. Our study aims to construct colon cancer metabolism-related molecular subtyping. Furthermore, to explore the metabolic heterogeneity in diverse colon cancer cells and illuminate the mechanisms of mitochondrial metabolic reprogramming. Thus, providing a theoretical basis for clinical nutritional therapy and combined intervention measures based on metabolic molecular phenotyping.
Methods
We selected 19 genes associated with glucose and the keto-body metabolic pathway, then constructed a prognostic gene signature by LASSO and KM curve. Based on the screened metabolic molecules, we further explored the nutrition metabolic heterogeneity and illuminate our understanding of mitochondrial metabolic reprogramming under nutritional stress in vivo.
Results
Through the integration of patients’ transcriptomics data, we stratified colon cancer patients into three significant phenotypes with distinct glycolytic and ketolytic characteristics. We identified glycolysis + subtype with either GLUT1 or PFKFB3 overexpression, and ketolysis + subtype with either OXCT1 or ACAT1 deficiency. In general, combining glycolysis+/ketolysis-phenotype demonstrated the worst prognosis. Furthermore, we discovered the metabolic heterogeneity through western blot and energy metabolic phenotype analysis which also confirmed that these different colon cancer cells showed great significance in metabolic reprogramming under nutritional stress.
Conclusions
The multi-target combination of metabolic phenotyping proved to be a foundation for individualized molecular stratified treatment which plays an essential role in predicting effectiveness of nutritional modulation therapy among colon cancer patients. It provided a theoretical basis for the clinical trial of KD therapy for patients with specific metabolic subtypes of colon cancer.
Funding Sources
The National Key Research and Development Program: The key technology of palliative care and nursing for cancer patients.
Differential expression of carcinoembryonic antigen (CEA) splice variants in whole blood of colon cancer patients and healthy volunteers: implication for the detection of circulating colon cancer cells