The ULK3 Kinase Is Critical for Convergent Control of Cancer-Associated Fibroblast Activation by CSL and GLI

Cell Rep. 2017 Sep 5;20(10):2468-2479. doi: 10.1016/j.celrep.2017.08.048.

Abstract

The connection between signaling pathways activating cancer-associated fibroblasts (CAFs) remains to be determined. Metabolic alterations linked to autophagy have also been implicated in CAF activation. CSL/RBPJ, a transcriptional repressor that mediates Notch signaling, suppresses the gene expression program(s), leading to stromal senescence and CAF activation. Deregulated GLI signaling can also contribute to CAF conversion. Here, we report that compromised CSL function depends on GLI activation for conversion of human dermal fibroblasts into CAFs, separately from cellular senescence. Decreased CSL upregulates the expression of the ULK3 kinase, which binds and activates GLI2. Increased ULK3 also induces autophagy, which is unlinked from GLI and CAF activation. ULK3 upregulation occurs in the CAFs of several tumor types, and ULK3 silencing suppresses the tumor-enhancing properties of these cells. Thus, ULK3 links two key signaling pathways involved in CAF conversion and is an attractive target for stroma-focused anti-cancer intervention.

Keywords: CAF; CSL/RBPJ; GLI; SCC; ULK3; autophagy; cancer stroma; cancer-associated fibroblast; squamous cell carcinoma; tumor microenvironment.

MeSH terms

  • Animals
  • Autophagy / physiology
  • Cancer-Associated Fibroblasts / metabolism*
  • Female
  • Fibroblasts / metabolism*
  • Fluorescent Antibody Technique
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Mice
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Zinc Finger Protein GLI1 / genetics
  • Zinc Finger Protein GLI1 / metabolism*

Substances

  • GLI1 protein, human
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • RBPJ protein, human
  • Zinc Finger Protein GLI1
  • Protein-Serine-Threonine Kinases
  • ULK3 protein, human