Dataset Information

Tumor-Stroma IL1?-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer.

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 NF?B activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NF?B. IRAK4 expression in CAF promoted NF?B activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1? as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1? rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1? expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL1?-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.Significance: Targeting the IL1?-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700-12. ©2018 AACR.

SUBMITTER: Zhang D

PROVIDER: S-EPMC5890818 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Tumor-Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer.

Zhang Daoxiang D Li Lin L Jiang Hongmei H Li Qiong Q Wang-Gillam Andrea A Yu Jinsheng J Head Richard R Liu Jingxia J Ruzinova Marianna B MB Lim Kian-Huat KH

Cancer research 20180123 7

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 ...[more]

PMID: 29363544

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Project description:The ability of tumors to survive therapy reflects both cell-intrinsic and microenvironmental mechanisms. Across many cancers, including triple-negative breast cancer (TNBC), a high stroma/tumor ratio correlates with poor survival. In many contexts, this correlation can be explained by the direct reduction of therapy sensitivity induced by stroma-produced paracrine factors. We sought to explore whether this direct effect contributes to the link between stroma and poor responses to chemotherapies. In vitro studies with panels of TNBC cell line models and stromal isolates failed to detect a direct modulation of chemoresistance. At the same time, consistent with prior studies, fibroblast-produced secreted factors stimulated treatment-independent enhancement of tumor cell proliferation. Spatial analyses indicated that proximity to stroma is often associated with enhanced tumor cell proliferation in vivo. These observations suggested an indirect link between stroma and chemoresistance, where stroma-augmented proliferation potentiates the recovery of residual tumors between chemotherapy cycles. To evaluate this hypothesis, a spatial agent-based model of stroma impact on proliferation/death dynamics was developed that was quantitatively parameterized using inferences from histologic analyses and experimental studies. The model demonstrated that the observed enhancement of tumor cell proliferation within stroma-proximal niches could enable tumors to avoid elimination over multiple chemotherapy cycles. Therefore, this study supports the existence of an indirect mechanism of environment-mediated chemoresistance that might contribute to the negative correlation between stromal content and poor therapy outcomes.SignificanceIntegration of experimental research with mathematical modeling reveals an indirect microenvironmental chemoresistance mechanism by which stromal cells stimulate breast cancer cell proliferation and highlights the importance of consideration of proliferation/death dynamics. See related commentary by Wall and Echeverria, p. 3667.

Dataset Information

Tumor-Stroma IL1?-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer.

Publications

Tumor-Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer.

Similar Datasets

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