Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, United States of America.
Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS Genet. 2022 Jul 22;18(7):e1010315. doi: 10.1371/journal.pgen.1010315. eCollection 2022 Jul.
Proper Hedgehog (HH) signaling is essential for embryonic development, while aberrant HH signaling drives pediatric and adult cancers. HH signaling is frequently dysregulated in pancreatic cancer, yet its role remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of HH transcription factors (GLI1, GLI2, GLI3), remain largely unexplored in pancreatic cancer. We therefore investigated the individual and combined contributions of GLI1-3 to pancreatic cancer progression. At pre-cancerous stages, fibroblast-specific Gli2/Gli3 deletion decreases immunosuppressive macrophage infiltration and promotes T cell infiltration. Strikingly, combined loss of Gli1/Gli2/Gli3 promotes macrophage infiltration, indicating that subtle changes in Gli expression differentially regulate immune infiltration. In invasive tumors, Gli2/Gli3 KO fibroblasts exclude immunosuppressive myeloid cells and suppress tumor growth by recruiting natural killer cells. Finally, we demonstrate that fibroblasts directly regulate macrophage and T cell migration through the expression of Gli-dependent cytokines. Thus, the coordinated activity of GLI1-3 directs the fibroinflammatory response throughout pancreatic cancer progression.
适当的 Hedgehog (HH) 信号对于胚胎发育至关重要，而异常的 HH 信号会导致小儿和成人生殖器癌症。HH 信号在胰腺癌中经常失调，但它的作用仍然存在争议，既有促进肿瘤的作用，也有抑制肿瘤的作用。值得注意的是，HH 转录因子家族的 GLI（GLI1、GLI2、GLI3）在胰腺癌中基本上尚未被探索。因此，我们研究了 GLI1-3 对胰腺癌进展的单独和联合作用。在癌前阶段，成纤维细胞特异性 Gli2/Gli3 缺失可减少免疫抑制性巨噬细胞浸润，并促进 T 细胞浸润。引人注目的是，Gli1/Gli2/Gli3 的联合缺失促进了巨噬细胞浸润，表明 Gli 表达的细微变化可不同程度地调节免疫浸润。在侵袭性肿瘤中，Gli2/Gli3 KO 成纤维细胞通过招募自然杀伤细胞排斥免疫抑制性髓样细胞并抑制肿瘤生长。最后，我们证明成纤维细胞通过表达Gli 依赖性细胞因子直接调节巨噬细胞和 T 细胞迁移。因此，GLI1-3 的协调活性指导了整个胰腺癌进展过程中的纤维炎性反应。
