Cutaneous Biology Research Center, Massachusetts General Hospital, 149 Bldg., 13th St. Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Boston, MA 02125, USA.
Department of Biochemistry, University of Lausanne, 155 Chemin des Boveresses, Epalinges 1066, Switzerland.
Cell Rep. 2017 Sep 5;20(10):2468-2479. 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.
信号通路激活癌症相关成纤维细胞（CAFs）之间的联系尚待确定。与自噬相关的代谢改变也与 CAF 激活有关。CSL/RBPJ 是一种转录抑制剂，介导 Notch 信号，抑制基因表达程序，导致基质衰老和 CAF 激活。失调控的 GLI 信号也可能导致 CAF 转化。在这里，我们报告说，CSL 功能的缺陷取决于 GLI 的激活，用于将人真皮成纤维细胞转化为 CAFs，与细胞衰老分开。CSL 减少上调 ULK3 激酶的表达，该激酶结合并激活 GLI2。增加 ULK3 也诱导与 GLI 和 CAF 激活无关的自噬。ULK3 的上调发生在几种肿瘤类型的 CAFs 中，并且 ULK3 的沉默抑制了这些细胞的肿瘤增强特性。因此，ULK3 将两个涉及 CAF 转化的关键信号通路联系起来，是一种有吸引力的针对基质的抗癌干预靶点。
