TLR9 ligation in pancreatic stellate cells promotes tumorigenesis.
Modulation of Toll-like receptor (TLR) signaling can have protective or protumorigenic effects on oncogenesis depending on the cancer subtype and on specific inflammatory elements within the tumor milieu. We found that TLR9 is widely expressed early during the course of pancreatic transformation and that TLR9 ligands are ubiquitous within the tumor microenvironment. TLR9 ligation markedly accelerates oncogenesis, whereas TLR9 deletion is protective. We show that TLR9 activation has distinct effects on the epithelial, inflammatory, and fibrogenic cellular subsets in pancreatic carcinoma and plays a central role in cross talk between these compartments. Specifically, TLR9 activation can induce proinflammatory signaling in transformed epithelial cells, but does not elicit oncogene expression or cancer cell proliferation. Conversely, TLR9 ligation induces pancreatic stellate cells (PSCs) to become fibrogenic and secrete chemokines that promote epithelial cell proliferation. TLR9-activated PSCs mediate their protumorigenic effects on the epithelial compartment via CCL11. Additionally, TLR9 has immune-suppressive effects in the tumor microenvironment (TME) via induction of regulatory T cell recruitment and myeloid-derived suppressor cell proliferation. Collectively, our work shows that TLR9 has protumorigenic effects in pancreatic carcinoma which are distinct from its influence in extrapancreatic malignancies and from the mechanistic effects of other TLRs on pancreatic oncogenesis.
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Constantinos P
CP
Zambirinis
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Elliot
E
Levie
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Susanna
S
Nguy
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Antonina
A
Avanzi
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Rocky
R
Barilla
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Yijie
Y
Xu
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Lena
L
Seifert
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Donnele
D
Daley
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Stephanie H
SH
Greco
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Michael
M
Deutsch
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Saikiran
S
Jonnadula
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Alejandro
A
Torres-Hernandez
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Daniel
D
Tippens
New York University College of Dentistry, New York, NY 10016.
Smruti
S
Pushalkar
Department of Surgery, New York University School of Medicine, New York, NY 10016.
Andrew
A
Eisenthal
New York University College of Dentistry, New York, NY 10016.
Deepak
D
Saxena
Department of Population Health, New York University School of Medicine, New York, NY 10016.
Jiyoung
J
Ahn
Department of Pathology, New York University School of Medicine, New York, NY 10016.
Cristina
C
Hajdu
Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724.
Dannielle D
DD
Engle
Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724.
David
D
Tuveson
Department of Surgery, New York University School of Medicine, New York, NY 10016 Department of Cell Biology, New York University School of Medicine, New York, NY 10016 george.miller@nyumc.org.
George
G
Miller
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D015151:Immunoblotting; D008024:Ligands; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
D054413:Chemokine CCL11; D018925:Chemokines; C423449:CpG ODN 1826; D008024:Ligands; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9