PTEN inhibits AMPK to control collective migration

Area of Science:

• Cancer Biology
• Cellular Metabolism
• Tumor Suppressor Genes

Background:

• PTEN (Phosphatase and Tensin homolog) is a critical tumor suppressor gene frequently altered in various cancers, including glioblastomas.
• The precise role of PTEN in collective cell migration and invasion remains incompletely understood, particularly in non-tumorous cells.

Purpose of the Study:

• To investigate the function of PTEN in collective cell migration and invasion.
• To elucidate the molecular mechanisms by which PTEN loss affects cell migration and invasion.
• To explore therapeutic strategies targeting PTEN-null glioblastoma invasiveness.

Main Methods:

• In vitro and in vivo assays to assess collective cell migration speed.
• Analysis of LKB1-dependent phosphorylation and activation of AMPK (AMP-activated protein kinase).
• Investigation of VASP phosphorylation and localization at cell-cell junctions.
• Assessment of actin dynamics at the leading front of migrating cells.
• Evaluation of therapeutic targeting of AMPK activity in PTEN-null glioblastoma cells.

Main Results:

• Loss of PTEN significantly increases cell speed during collective migration in both in vitro and in vivo models.
• PTEN loss promotes LKB1-dependent phosphorylation and activation of AMPK.
• AMPK activation leads to increased VASP phosphorylation, reduced VASP at cell-cell junctions, and decreased transverse actin arcs.
• These molecular changes result in weakened cell-cell contacts and enhanced migration speed.
• Targeting AMPK activity effectively slows PTEN-depleted cells and reduces glioblastoma cell invasion.

Conclusions:

• PTEN loss enhances collective cell migration and invasion through an LKB1-AMPK-VASP signaling axis.
• This pathway involves metabolic regulation impacting cell-cell adhesion and motility.
• Targeting AMPK offers a promising therapeutic strategy to inhibit glioblastoma invasiveness.