TLR9 ligation in pancreatic stellate cells promotes tumorigenesis

Zambirinis, Constantinos P.; Levie, Elliot; Nguy, Susanna; Avanzi, Antonina; Barilla, Rocky; Xu, Yijie; Seifert, Lena; Daley, Donnele; Greco, Stephanie H.; Deutsch, Michael; Jonnadula, Saikiran; Torres‐Hernandez, Alejandro; Tippens, Daniel; Pushalkar, Smruti; Eisenthal, Andrew; Saxena, Deepak; Ahn, Jiyoung; Hajdu, Cristina; Engle, Dannielle D.; Tuveson, David A.; Miller, George

doi:10.1083/jcb.2112oia232

Cited by 23 publications

(34 citation statements)

References 23 publications

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“…6 TLR agonists also promote increased tumor invasion in vitro in breast cancer and metastasis in vivo in pancreatic and colorectal cancer. [7][8][9] Moreover, circulating levels of innate TLR agonists, including cell-free nucleic acids and associated complexes, are elevated in a multitude of cancers and can further increase following chemotherapy, radiation, and surgery. [9][10][11][12] These endogenous factors can circulate alone or on/within lipid microvesicles, such as microparticles or exosomes, to induce pro-tumorigenic signaling in cancer cells and the tumor microenvironment and precondition secondary sites for metastatic establishment.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12] These endogenous factors can circulate alone or on/within lipid microvesicles, such as microparticles or exosomes, to induce pro-tumorigenic signaling in cancer cells and the tumor microenvironment and precondition secondary sites for metastatic establishment. [6][7][8][13][14][15][16][17] Recent work has highlighted specific contributions of TLR activation mediated by circulating nucleic acid DAMPs to disease progression in pancreatic cancer (PC), 7,13,15 which has the worst prognosis of all major cancers due in part to its aggressive, metastatic nature. 18,19 Surgical resection is the only potentially curative treatment option.…”

Section: Introductionmentioning

confidence: 99%

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Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis

et al. 2018

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Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3 generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells in vitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis

et al. 2018

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“…For instance, ligation of TLR4 enhances the invasiveness of PDAC cells in an NF-κB-dependent manner(13). In genetically-engineerd mouse models, ligation of TLR7 or TLR9 accelerates stromal inflammation and progression of PDAC activation of the NF-κB and MAPK pathways(14, 15). However, the intrinsic role of TLR signaling in neoplastic PDAC cells and how it affects the extrinsic tumor microenvironemt have not been thoroughly described.…”

Section: Introductionmentioning

confidence: 99%

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma

Zhang

Jiang

et al. 2017

Clinical Cancer Research

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Purpose Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the Interleukin-1 Receptor-Associated Kinase (IRAK) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAK in the pathobiology of PDAC. Experimental Design We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small molecule IRAK1/4 inhibitor, RNA-interference and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production and growth of PDAC cells in vitro and in vivo. Results p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. Presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance and secretion of pro-inflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing.

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“…However, clinical benefit of this strategy is currently unproven and concerns regarding off-target effects persist. Pro-tumor roles have been demonstrated for both TLR7/8 (Ochi, et al, 2012) and TLR9 (Zambirinis, et al, 2015) ligation in the PC microenvironment. Thus, further investigation remains to be done to delineate the clinical efficacy of TLR stimulation in PC or other solid neoplasms.…”

Section: Modulators Of Innate Immunitymentioning

confidence: 98%