Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis

Wilmerding, A.; Bouteille, L.; Caruso, N.; Bidaut, G.; Etchevers, H. C.; Graba, Y.; DELFINI, M.-C.

doi:10.1101/2021.06.10.447891

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bioRxiv · 10.1101/2021.06.10.447891

Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis

Wilmerding, A.·Bouteille, L.·Caruso, N.·Bidaut, G.·Etchevers, H. C.·Graba, Y.·DELFINI, M.-C.

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Abstract

Most human cancers demonstrate activated MAPK/ERK pathway signaling as a key tumor initiation step, but the immediate steps of further oncogenic progression are poorly understood due to a lack of appropriate models. Spinal cord differentiation follows caudal elongation in vertebrate embryos; both processes are regulated by a FGF8 gradient highest in neuromesodermal progenitors (NMP), where kinase effectors ERK1/2 maintain an undifferentiated state. FGF8/ERK signal attenuation is necessary for NMPs to progress to differentiation. We show that sustained ERK1/2 activity, using a constitutively active form of the kinase MEK1 (MEK1ca) in the chicken embryo, reproducibly provokes neopasia in the developing spinal cord. Transcriptomic data show that neoplasia not only relies on the maintenance of NMP gene expression, and the inhibition of genes expressed in the differentiating spinal cord, but also on a profound change in the transcriptional signature of the spinal cord cells leading to a complete loss of cell-type identity. MEK1ca expression in the developing spinal cord of the chicken embryo is therefore a tractable in vivo model to identify the critical factors fostering malignancy in ERK-induced tumorigenesis.

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Wilmerding, A., Bouteille, L., Caruso, N., Bidaut, G., Etchevers, H. C., Graba, Y., DELFINI, M.-C.. 2021-06-10. Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis. https://doi.org/10.1101/2021.06.10.447891

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