N isotopes in Human Models
​Cancerous cells can recycle metabolic ammonium for their growth. As this ammonium has a low nitrogen isotope ratio (15N/14N), we hypothesize that its recycling may cause cancer tissue to have lower 15N/14N than surrounding healthy tissue. If true, the distinct 15N/14N signature of cancer tissue could be used as a new diagnostic tool. We are currently investigating this hypothesis by measuring the isotopic composition of healthy and cancerous tissue in human micro-biopsies with a novel highly sensitive technique.
Nitrogen isotopic composition as a gauge of tumor cell anabolism‑to‑catabolism ratio
Studies have suggested that cancerous tissue has a lower 15N/14N ratio than benign tissue. However, human data have been inconclusive, possibly due to constraints on experimental design. In a recent study, we used high-sensitivity nitrogen isotope methods to assess the 15N/14N ratio of human breast, lung, and kidney cancer tissue at unprecedented spatial resolution (Straub et al. 2023). In lung, breast, and urothelial carcinoma, 15N/14N was negatively correlated with tumor cell density. The magnitude of 15N depletion for a given tumor cell density was consistent across different types of lung cancer, ductal in situ and invasive breast carcinoma, and urothelial carcinoma, suggesting similar elevations in the anabolism-to-catabolism ratio. However, tumor 15N depletion was higher in a more aggressive metaplastic breast carcinoma. These findings may indicate the ability of certain cancers to more effectively channel N towards growth. Our results support 15N/14N analysis as a potential tool for screening biopsies and assessing N metabolism in tumor cells.
N isotopic composition of Benign minus Cancerous tissue normalized to Tumor Cell Density, this metric indicates the level of 15N depletion of a cancer cell with respect to a normal cell, for individual patients and cancer types (Straub et al. 2023)
Hypothetical scenarios of N metabolism compared with predicted and observed δ15N differences between benign and cancerous tissues from the same organ (δ15NB-C). (a) Benign cell metabolism, with normal ammonium efflux (Befflux). (b) Scenario of cancerous cells with higher anabolism-to-catabolism ratio, in which 50% of the N supply is incorporated into growth. (c) Scenario of cancerous cells with highest anabolism-to-catabolism ratio, in which 100% of the N supply is ultimately used for growth. Table lines with grey background indicate the expected δ15NB-C for each scenario assuming an isotope effect (ε) for catabolic ammonium production of 3–4‰. Text with blue background indicates the measured δ15NB-C for each cancer type (Straub et al 2023)