Ultrasensitive Luminescence-based Yeast Sensors for Specific Early Cancer Sensing

ULYSSES is a pioneering project aimed at developing a non-invasive, portable, and user-friendly biosensor for the early detection of breast and prostate cancers through urine analysis. Its core vision is to identify cancer-related volatile organic compounds (VOCs) and develop a biotechnological device for their detection in urine. The innovation lies in mimicking the extraordinary olfactory system of the nematode Caenorhabditis elegans, which can distinguish cancerous from healthy urine with over 90% accuracy. This ability is mediated by a large repertoire of olfactory receptors (ORs) expressed on specialized sensory neurons. ULYSSES replicates this sensing capacity in a synthetic biology framework by introducing selected C. elegans ORs into engineered yeast (Saccharomyces cerevisiae). These ORs are functionally coupled to a bioluminescence resonance energy transfer (BRET)-based biosensing construct. Upon binding cancer-associated VOCs, conformational changes in the ORs trigger measurable BRET signal shifts, serving as indicators of cancer-specific profiles with nanomolar sensitivity. In parallel, urine VOCs will be analysed via gas chromatography–mass spectrometry (GC-MS). Machine learning will be applied to the spectral data to identify key compounds that differentiate cancer from healthy samples and link them to specific OR activation profiles. Engineered yeast biosensors, each with a distinct OR-BRET construct, will be arrayed on a disposable device. Upon urine exposure, BRET signal changes will be recorded and interpreted via an AI algorithm trained on activation heatmaps. This enables the identification of cancer-related patterns with high sensitivity and specificity. Feasibility is ensured by the convergence of expertise within a strongly interdisciplinary consortium. ULYSSES lays the foundation for a versatile diagnostic platform with broad applications in health monitoring and personalized medicine, with strong potential for societal and healthcare impact.