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

Neoplasia. 2022 Feb;24(2):120-132. doi: 10.1016/j.neo.2021.12.006. Epub 2021 Dec 24.

Abstract

The MAPK/ERK pathway regulates a variety of physiological cellular functions, including cell proliferation and survival. It is abnormally activated in many types of human cancers in response to driver mutations in regulators of this pathway that trigger tumor initiation. The early steps of oncogenic progression downstream of ERK overactivation are poorly understood due to a lack of appropriate models. We show here that ERK1/2 overactivation in the trunk neural tube of the chicken embryo through expression of a constitutively active form of the upstream kinase MEK1 (MEK1ca), rapidly provokes a profound change in the transcriptional signature of developing spinal cord cells. These changes are concordant with a previously established role of the tyrosine kinase receptor ligand FGF8 acting via the ERK1/2 effectors to maintain an undifferentiated state. Furthermore, we show that MEK1ca-transfected spinal cord cells lose neuronal identity, retain caudal markers, and ectopically express potential effector oncogenes, such as AQP1. MEK1ca expression in the developing spinal cord from the chicken embryo is thus a tractable in vivo model to identify the mechanisms fostering neoplasia and malignancy in ERK-induced tumorigenesis of neural origins.

Keywords: Cancer model; Chicken embryo; Developing spinal cord; MAPK/ERK pathway; MEK1 (MAP2K1); Neural crest cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / metabolism*
  • Chickens
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fibroblast Growth Factor 8 / metabolism*
  • Humans
  • Signal Transduction*
  • Spinal Cord / metabolism*
  • Spinal Cord / pathology

Substances

  • Fibroblast Growth Factor 8
  • Extracellular Signal-Regulated MAP Kinases