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

• Published in: Cell reports (Cambridge) 2017-09, Vol.20 (10), p.2468-2479
• Main Authors: Goruppi, Sandro, Procopio, Maria-Giuseppina, Jo, Seunghee, Clocchiatti, Andrea, Neel, Victor, Dotto, G. Paolo
• Format: Article
• Language: English
• Subjects: Animals; autophagy; Autophagy - physiology; CAF; cancer stroma; cancer-associated fibroblast; Cancer-Associated Fibroblasts - metabolism; CSL/RBPJ; Female; Fibroblasts - metabolism; Fluorescent Antibody Technique; GLI; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Mice; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; SCC; Signal Transduction - genetics; Signal Transduction - physiology; squamous cell carcinoma; tumor microenvironment; ULK3; Zinc Finger Protein GLI1 - genetics; Zinc Finger Protein GLI1 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.08.048

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. [Display omitted] •CAF conversion by loss of CSL depends on GLI activation•CSL functions as a negative regulator of the pro-autophagy kinase ULK3•Increased ULK3 induces GLI2-dependent CAF activation separately from autophagy•Silencing of ULK3 in SCC-derived CAFs suppresses their tumor-enhancing properties Goruppi et al. demonstrate that CSL, a transcriptional repressor mediating Notch signaling, suppresses the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) by controlling the expression of autophagy kinase ULK3, which, in turn, activates GLI signaling. Their studies connect two key pathways involved in CAF activation and identify a target for stroma-focused anti-cancer intervention.