Combinatorial Gli activity directs immune infiltration and tumor growth in pancreatic cancer.

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.

CDON contributes to Hedgehog-dependent patterning and growth of the developing limb.

Hedgehog (HH) signaling is a major driver of tissue patterning during embryonic development through the regulation of a multitude of cell behaviors including cell fate specification, proliferation, migration, and survival. HH ligands signal through the canonical receptor PTCH1 and three co-receptors, GAS1, CDON and BOC. While previous studies demonstrated an overlapping and collective requirement for these co-receptors in early HH-dependent processes, the early embryonic lethality of Gas1;Cdon;Boc mutants precluded an assessment of their collective contribution to later HH-dependent signaling events. Specifically, a collective role for these co-receptors during limb development has yet to be explored. Here, we investigate the combined contribution of these co-receptors to digit specification, limb patterning and long bone growth through limb-specific conditional deletion of Cdon in a Gas1;Boc null background. Combined deletion of Gas1, Cdon and Boc in the limb results in digit loss as well as defects in limb outgrowth and long bone patterning. Taken together, these data demonstrate that GAS1, CDON and BOC are collectively required for HH-dependent patterning and growth of the developing limb.

Bisphenol F has different effects on preadipocytes differentiation and weight gain in adult mice as compared with Bisphenol A and S.

Bisphenol S (2,2-bisulfone, BPS) and Bisphenol F (2,2-bis [4-hydroxyphenol]methane, BPF) are analogs of Bisphenol A (2,2-bis[4-hydroxyphenyl]propane, BPA), a widely used endocrine disrupting compound present in polycarbonate plastics, thermal receipts and epoxy resins that line food cans. Here we examined effects of BPA, BPS, and BPF in low concentrations on differentiation in murine 3T3-L1 preadipocytes. We also fed adult male mice chow with one of three doses of BPF (0, 0.5, 5, 50 mg/kg chow, or approximately 0.044, 0.44 and 4.4 mg/kg body weight per day) for 12 weeks, collected body weights, food intake, and tested for glucose tolerance. The doses of BPF used produced mean concentrations of 0, 6.2, 43.6, and 561 ng/mL in plasma. In 3T3-L1 cells BPS had the greatest effects, along with BPA, both increased expression of several genes required for preadipocyte differentiation over 12 days in culture. In contrast, BPF decreased expression of several genes late in differentiation. This dichotomy was also reflected in lipid accumulation as BPA and BPS treated cells had elevated lipid concentrations compared to controls or cells treated with BPF. Male mice fed either the highest or lowest concentrations of BPF gained less weight than controls with no effects on glucose levels or glucose tolerance. Plasma levels of BPF reflected doses in food with no overlap between doses. In summary, our results suggest that BPS has a strong potential to be obesogenic while effects of BPF are subtler and potentially in the opposite direction.