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Members of the EGF-CFC (Cripto, FRL-1, Cryptic) protein family are increasingly recognized as key mediators of cell movement and cell differentiation during vertebrate embryogenesis. The founding member of this protein family, CRIPTO, is overexpressed in various human carcinomas. Yet, the biological role of CRIPTO in this setting remains unclear. Here, we find CRIPTO expression as especially high in a subgroup of primary prostate carcinomas with poorer outcome, wherein resides cancer cell clones with mesenchymal traits. Experimental studies in PCa models showed that one notable function of CRIPTO expression in prostate carcinoma cells may be to augment PI3K/AKT and FGFR1 signaling, which promotes epithelial-mesenchymal transition and sustains a mesenchymal state. In the observed signaling events, FGFR1 appears to function parallel to AKT, and the two pathways act cooperatively to enhance migratory, invasive and transformation properties specifically in the CRIPTO overexpressing cells. Collectively, these findings suggest a novel molecular network, involving CRIPTO, AKT, and FGFR signaling, in favor of the emergence of mesenchymal-like cancer cells during the development of aggressive prostate tumors.

Many solid cancers are hierarchically organized with a small number of cancer stem cells (CSCs) able to regrow a tumor, while their progeny lacks this feature. Breast CSC is known to contribute to therapy resistance. The study of those cells is usually based on their cell‐surface markers like CD44high/CD24low/neg or their aldehyde dehydrogenase (ALDH) activity. However, these markers cannot be used to track the dynamics of CSC. Here, a transcriptomic analysis is performed to identify segregating gene expression in CSCs and non‐CSCs, sorted by Aldefluor assay. It is observed that among ALDH‐associated genes, only ALDH1A1 isoform is increased in CSCs. A CSC reporter system is then developed by using a far red‐fluorescent protein (mNeptune) under the control of ALDH1A1 promoter. mNeptune‐positive cells exhibit higher sphere‐forming capacity, tumor formation, and increased resistance to anticancer therapies. These results indicate that the reporter identifies cells with stemness characteristics. Moreover, live tracking of cells in a microfluidic system reveals a higher extravasation potential of CSCs. Live tracking of non‐CSCs under irradiation treatment show, for the first time, live reprogramming of non‐CSCs into CSCs. Therefore, the reporter will allow for cell tracking to better understand the implication of CSCs in breast cancer development and recurrence.

This article has been corrected: During the assembly of the Figure 5 panel I, low magnification images (2x objective) from the same condition SB431542 were inadvertently used for both the vehicle DMSO and SB431432 treated 22Rv1/CR-1 cells. Similarly, the low magnification image (2x objective) from LY294002 treated 22rv1/vector was inadvertently used for both LY294002 and U0126 treated cells. The corrected Figure 5 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.

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