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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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE262362 | GEO | 2024/12/04

REPOSITORIES: GEO

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Project description:Predicting Outcomes of Prostate Cancer Immunotherapyby Personalized Mathematical Models Natalie Kronik1¤, Yuri Kogan1, Moran Elishmereni1, Karin Halevi-Tobias1, Stanimir Vuk-Pavlovic ́2.,Zvia Agur1*.1Institute for Medical BioMathematics, Bene Ataroth, Israel,2College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America Abstract Background:Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients.We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simplemathematical models.Methodology/Principal Findings:We developed a general mathematical model encompassing the basic interactions of avaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cellvaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes inprostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were dividedinto each patient’s training set and his validation set. The training set, used for model personalization, contained thepatient’s initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized modelswere simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set.The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients(the coefficient of determination between the predicted and observed PSA values wasR2= 0.972). The model could notaccount for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validatedpersonalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccinationregimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Conclusions/Significance:Using a few initial measurements, we constructed robust patient-specific models of PCaimmunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value andfeasibility of individualized model-suggested immunotherapy protocols.

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

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