Microenvironment-Driven Shift of Cohesion/Detachment Balance within Tumors Induces a Switch toward Metastasis in Neuroblastoma

Cancer Cell. 2017 Oct 9;32(4):427-443.e8. doi: 10.1016/j.ccell.2017.09.006.

Abstract

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. Disseminated forms have high frequency of multiple tumoral foci whose etiology remains unknown; NB embryonic origin limits investigations in patients and current models. We developed an avian embryonic model driving human NB tumorigenesis in tissues homologous to patients. We found that aggressive NBs display a metastatic mode, secondary dissemination via peripheral nerves and aorta. Through tumor transcriptional profiling, we found that NB dissemination is induced by the shutdown of a pro-cohesion autocrine signal, SEMA3C, which constrains the tumoral mass. Lowering SEMA3C levels shifts the balance toward detachment, triggering NB cells to collectively evade the tumor. Together with patient cohort analysis, this identifies a microenvironment-driven pro-metastatic switch for NB.

Keywords: animal model; collective migration; embryonal cancer; metastatic switch; microenvironment; neural crest; neuroblastoma; neuroblastoma cell cohesion; plexin; semaphorin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Cell Adhesion
  • Chick Embryo
  • Child
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Neoplasm Staging
  • Nerve Tissue Proteins / physiology
  • Neuroblastoma / etiology
  • Neuroblastoma / pathology
  • Neuroblastoma / secondary*
  • Receptors, Cell Surface / physiology
  • Semaphorins / genetics
  • Semaphorins / physiology
  • Tumor Microenvironment*

Substances

  • Nerve Tissue Proteins
  • PLXNA2 protein, human
  • Receptors, Cell Surface
  • Sema3C protein, human
  • Semaphorins