Oncometabolite signatures from tumor-stroma crosstalk as potential non-invasive biomarkers

Tumor metabolism, a crucial component in cancer progression, represents a potential prognostic and diagnostic platform in cancer detection. Here, we show that patient-specific stromal mesenchymal cells exhibit distinct behaviors in promoting either tumor growth or dissemination. Tumor-associated fibroblasts (TAFs) isolated from non-metastasized colorectal adenocarcinomas predominantly supported cancer cell proliferation, whereas TAFs isolated from metastatic adenocarcinomas facilitated cancer cell migration. An in vitro analysis of stromal paracrine factors revealed that variations in mitochondrial activity and the secretion of specific metabolites were closely associated with distinct tumor-stroma interactions. Among the oncometabolites identified, we validated amino acid expression in urine samples from 19 colon cancer patients to assess their potential as diagnostic biomarkers. Our results showed patient-specific alterations in oncometabolite expression, which were significantly different from those of healthy control individuals. The specificity, sensitivity, and accuracy analysis indicated 93-100% specificity, 74-82% sensitivity, and 84-89% accuracy of single metabolites in distinguishing cancer patients from healthy controls. While no false negatives were observed, urine samples from nine patients with various inflammatory conditions (including diverticulitis, appendicitis, and chronic gastritis) yielded false positives. Sensitivity analysis and the t-Distributed Stochastic Neighbor Embedding (t-SNE) nonlinear dimensionality reduction technique revealed distinct metabolite profiles for healthy controls, colon cancer patients, and patients diagnosed with inflammation. Overall, our findings suggest that the identified oncometabolites, when integrated into a biomarker panel, hold promise as a novel non-invasive tool for screening individuals at risk of cancer and inflammatory malignancies.