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

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. To further study CRIPTO signaling in vivo, we developed new genetically engineered mouse models (GEMMs) in which we genetically knocked out CRIPTO to specifically investigate its role in castration-resistant Nkx3.1 expressing cells (CARNs), which are targeted for oncogenic transformation in prostate cancer (PCa). The most aggressive stage was modeled using an inducible Cre driver, Pten inactivation, oncogenic Kras activation, and lineage tracing with yellow fluorescence protein (E-YFP). Our findings provide evidence that selective depletion of CRIPTO in epithelial cells in vivo reduces 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 which was further associated with PSA progression in a human PCa cohort. Transcriptomic analysis of organoids derived from prostates of genetically engineered mice (N, NC, NP, NPC, NPK, NPKC) and transcriptomic analysis of tissues of NPKC mice treated with Alk4Fc.