Biology subjects

DELFINI, M.-C.

Publications and source records attributed to DELFINI, M.-C..

2 recordsLinked to original sources

bioRxiv2021

HOXB8 counteracts MAPK/ERK oncogenic signaling in a chicken embryo model of neoplasia

HOX transcription factors are members of an evolutionarily conserved family of proteins required for the establishment of the anteroposterior body axis during bilaterian development. Although they are often deregulated in cancers, the molecular mechanisms by which they act as oncogenes or tumor suppressor genes are only partially understood. Since the MAPK/ERK signaling pathway is deregulated in most cancers, we aimed at apprehending if and how Hox proteins interact with ERK oncogenicity. Using an in vivo neoplasia model in the chicken embryo that we have developed, consisting in the overactivation of the ERK1/2 kinases in the trunk neural tube, we analyzed the consequences of HOXB8 gain of function at morphological and transcriptional level in this model. We found that HOXB8 acts as a tumor suppressor, counteracting ERK-induced neoplasia. HOXB8 tumor suppressor function in this model relies on a large reversion of the oncogenic transcriptome induced by ERK. In addition to showing that HOXB8 protein controls the transcriptional responsiveness to ERK oncogenic signaling, our study identified new downstream targets of ERK oncogenic activation in an in vivo context that could provide clues for therapeutic strategies.

cancer biology↗

bioRxiv2021

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

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.

developmental biology↗