F. Vannuccini, Y. Ciani, V. Mugoni, O. Quaini, F. Orlando, V. Weber, A. C. Martinez, A. Martinelli, E. Biada, A. Marinelli, I. Casanova-Salas, F. Pessina, D. Di Vizio, A. Vannini, P. Cremaschi, S. Lise, C. Nardella, U. De Giorgi, C. Buttigliero, O. Caffo, U. Basso, J. Mateo, G. Attard, F. Demichelis
Circulating analytes in cancer patients capture tumor-related signals. We profiled matched extracellular vesicle (EV) total RNA and cell-free DNA (cfDNA) from the same plasma aliquots of chemo-naive metastatic castration-resistant prostate cancer (mCRPC) patients treated with Enzalutamide (n=54 patients, n=119 longitudinal samples; NCT06981377) at four Italian clinical centers and interrogated data from >10,000 cancer patients' and healthy individuals' samples. Transcript integrity analysis identified coding and non-coding species with fragmentation patterns varying across RNA biotypes. EV-RNA data deconvolution revealed signal from immune populations, including fractions classified as CD4+ T cells, whose abundance increased with disease progression in plasma EVs and mCRPC tissues. By leveraging tissue data-informed mining, we established a novel prostate cancer-related EV-RNA signature that resulted in an independent predictor of poor prognosis and captured tumor microenvironment-derived signals. Integrating EV-RNA and ctDNA information improved patient stratification for progression-free survival. These findings suggest a multifaceted role for plasma EVs as a source of cancer biomarkers.