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

Cell Reports

G. Paolo Dotto¹  Seunghee Jo¹  Andrea Clocchiatti¹  Sandro Goruppi¹  Maria-Giuseppina Procopio²  Victor Neel³ 

[1] Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA;Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, Epalinges 1066, Switzerland;Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA;

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

DOI  :  10.1016/j.celrep.2017.08.048

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown