| Autor: |
Julia E Lefler, Catherine B MarElia-Bennett, Katie A Thies, Blake E Hildreth, Sudarshana M Sharma, Jason R Pitarresi, Lu Han, Caroline Everett, Christopher Koivisto, Maria C Cuitino, Cynthia D Timmers, Elizabeth O’Quinn, Melodie Parrish, Martin J Romeo, Amanda J Linke, G Aaron Hobbs, Gustavo Leone, Denis C Guttridge, Teresa A Zimmers, Gregory B Lesinski, Michael C Ostrowski |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Life Science Alliance. 5:e202201460 |
| ISSN: |
2575-1077 |
| Popis: |
Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. Here, we show that disruption of the STAT3 signaling axis via genetic ablation ofStat3in stromal fibroblasts in aKrasG12DPDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immune-suppressive TME by decreasing M2 macrophages (F480+CD206+) and increasing CD8+T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. In addition, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results provide a potential mechanism by which CAFs promote an immune-suppressive TME and promote tumor progression in a spontaneous model of PDAC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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