TY - JOUR
T1 - STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer
AU - Lefler, Julia E.
AU - MarElia-Bennett, Catherine B.
AU - Thies, Katie A.
AU - Hildreth, Blake E.
AU - Sharma, Sudarshana M.
AU - Pitarresi, Jason R.
AU - Han, Lu
AU - Everett, Caroline
AU - Koivisto, Christopher
AU - Cuitino, Maria C.
AU - Timmers, Cynthia D.
AU - O'Quinn, Elizabeth
AU - Parrish, Melodie
AU - Romeo, Martin J.
AU - Linke, Amanda J.
AU - Aaron Hobbs, G.
AU - Leone, Gustavo
AU - Guttridge, Denis C.
AU - Zimmers, Teresa A.
AU - Lesinski, Gregory B.
AU - Ostrowski, Michael C.
N1 - Publisher Copyright:
© 2022 Rockefeller University Press. All rights reserved.
PY - 2022/11
Y1 - 2022/11
N2 - 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 contextdependent 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 of Stat3 in stromal fibroblasts in a KrasG12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immunesuppressive 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.
AB - 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 contextdependent 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 of Stat3 in stromal fibroblasts in a KrasG12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immunesuppressive 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.
UR - http://www.scopus.com/inward/record.url?scp=85134426331&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134426331&partnerID=8YFLogxK
U2 - 10.26508/lsa.202201460
DO - 10.26508/lsa.202201460
M3 - Article
C2 - 35803738
AN - SCOPUS:85134426331
SN - 2575-1077
VL - 5
JO - Life science alliance
JF - Life science alliance
IS - 11
M1 - e202201460
ER -