CRIPTO’s multifaceted role in driving aggressive prostate cancer unveiled by in vivo, organoid, and patient data

Abstract CRIPTO (or CR-1 or TDGF1) is a protein that plays an active role in tumor initiation and progression. We have confirmed that increased expression of CRIPTO is associated with clinical and prostate-specific antigen (PSA) progression in human prostate tissues. Our approach involved gaining insight into the role of CRIPTO signaling in castration-resistant Nkx3.1- expressing cells (CARNs), targets for oncogenic transformation in prostate cancer (PCa), by integrating the existing Cripto flox/flox into CARNs model. The most aggressive stage was modeled using an inducible Cre under control of the Nkx3.1 promoter conferring Nkx3.1 inactivation and driving Pten inactivation, oncogenic Kras activation, and lineage tracing with yellow fluorescence protein (EYFP) upon induction. Our findings provide evidence that selective depletion of Cripto in epithelial cells in vivo reduced the invasive phenotype, particularly in more advanced tumor stages. Moreover, in vitro experiments with Cripto overexpression demonstrated alterations in the physical features of organoids, which correlated with increased tumorigenic activity. Transcriptomic analyses revealed a unique CRIPTO/MYC co-activation signature associated with PSA progression in a human PCa cohort. Taken together, our data highlights a role for CRIPTO in tumor invasiveness and progression, which carries implications for biomarkers and targeted therapies.