Scales MK, Velez-Delgado A, Steele NG, Schrader HE, Stabnick AM, Yan W, Mercado Soto NM, Nwosu ZC, Johnson C, Zhang Y, Salas-Escabillas DJ, Menjivar RE, Maurer HC, Crawford HC, Bednar F, Olive KP, Pasca di Magliano M, and Allen BL. Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer. PLoS Genet 2022; 18(7):e1010315.
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.
Medical Subject Headings
Adult; Child; Female; Hedgehog Proteins; Humans; Kruppel-Like Transcription Factors; Nerve Tissue Proteins; Pancreatic Neoplasms; Pregnancy; Zinc Finger Protein GLI1; Zinc Finger Protein Gli2; Zinc Finger Protein Gli3