Rodrigues Sousa Elisa, de Brot Simone, Zoni Eugenio, Zeinali Soheila, Brunello Andrea, Scarpa Mario, De Menna Marta, La Manna Federico, Abey Alexander Allen, Klima Irena, Freeman David W, Gates Brooke L, Cristaldi Domenico A, Guenat Olivier T, Kruithof Boudewijn P T, Spike Benjamin T, Chouvardas Panagiotis, Kruithof-de Julio Marianna
Urology Research Laboratory, Department for BioMedical Research, University of Bern, Bern, Switzerland.
COMPATH, Institute of Animal Pathology, University of Bern, Bern, Switzerland.
Oncogene. 2025 Mar;44(7):462-475. doi: 10.1038/s41388-024-03230-x. Epub 2024 Nov 26.
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 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.
CRIPTO（或CR-1或TDGF1）是一种在肿瘤起始和进展中发挥积极作用的蛋白质。我们已经证实，CRIPTO表达增加与人类前列腺组织中的临床进展及前列腺特异性抗原（PSA）进展相关。我们的方法包括通过将现有的Cripto整合到去势抵抗性Nkx3.1表达细胞（CARNs）模型中，来深入了解CRIPTO信号在CARNs中的作用，CARNs是前列腺癌（PCa）致癌转化的靶点。最具侵袭性的阶段通过在Nkx3.1启动子控制下使用诱导型Cre进行建模，该启动子可导致Nkx3.1失活，并在诱导时驱动Pten失活、致癌性Kras激活以及用黄色荧光蛋白（EYFP）进行谱系追踪。我们的研究结果表明，体内上皮细胞中Cripto的选择性缺失可降低侵袭性表型，尤其是在更晚期的肿瘤阶段。此外，Cripto过表达的体外实验表明类器官的物理特征发生了改变，这与致瘤活性增加相关。转录组分析揭示了在人类PCa队列中与PSA进展相关的独特的CRIPTO/MYC共激活特征。综上所述，我们的数据突出了CRIPTO在肿瘤侵袭和进展中的作用，这对生物标志物和靶向治疗具有启示意义。
