Tumor–Stroma IL1b-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer

Daoxiang Zhang, Lin Li, Hongmei Jiang, Qiong Li, Andrea Wang-Gillam, Jinsheng Yu, Richard Head, Jingxia Liu, Marianna B. Ruzinova, Kian Huat Lim

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor–associated kinase 4 (IRAK4) suppresses NFkB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFkB. IRAK4 expression in CAF promoted NFkB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1b as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1b rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1b expression associated strongly with poor overall survival. Together, our studies establish a tumor–stroma IL1b-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC. Significance: Targeting the IL1b-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer.

Original languageEnglish
Pages (from-to)1700-1712
Number of pages13
JournalCancer research
Volume78
Issue number7
DOIs
StatePublished - Apr 2018

Fingerprint Dive into the research topics of 'Tumor–Stroma IL1b-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer'. Together they form a unique fingerprint.

  • Cite this