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| Status |
Public on Jan 26, 2018 |
| Title |
Tumor-stroma IL-1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemo-resistance and Poor Prognosis in Pancreatic Cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but so far success remains limited in the clinic. Furthermore, preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAFs) carries a risk of accelerating PDAC progression. These concerns underscore the need to concurrently target the key signaling mechanisms that drive the malignant attributes of both CAFs and PDAC cells. We previously reported that inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) suppresses NF-kB activity and promotes chemotherapy response in PDAC cells. In this study, we show that CAFs in PDAC tumors robustly express activated IRAK4 and NF-kb. The role of IRAK4 and NF-kB in PDAC CAFs has not been reported, and should be clarified before advancing IRAK4 inhibitors to the clinic. Using shRNAs and small molecular inhibitors, we found that IRAK4 is a key driver of NF-kB activity in CAFs. We showed that CAFs utilizes IRAK4 to drive tumor fibrosis, support PDAC cells proliferation, survival and chemoresistance in vitro and in vivo. From cytokine array analysis of CAFs and microarray analysis of PDAC cells, we identified IL-1b as a key cytokine that activates IRAK4 in CAFs. Targeting IRAK4 or IL-1b renders PDAC tumors less fibrotic and more sensitive to gemcitabine in vivo. Moreover, high IL-1b expression by immunohistochemistry in PDAC stroma is strongly associated with poor overall survival. Together, our studies established a tumor-stroma IL-1b-IRAK4 feedforward circuitry that can be therapeutically disrupted to render chemotherapy more effective in PDAC.
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| Overall design |
We use both pharmacological and shRNA approaches to explore the contribution of IRAK1/4 inhibition in pancreatic cancer cells. For pharmacological approach, we use PANC-1 and Capan-1 for study since these two cell lines express activated form of IRAK1 and IRAK4. For shRNA approach, we use PANC-1 for analysis.
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| Contributor(s) |
Lim K, Zhang D |
| Citation(s) |
29363544 |
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| Submission date |
Sep 15, 2015 |
| Last update date |
Apr 27, 2018 |
| Contact name |
Jinsheng Yu |
| E-mail(s) |
jyu@wustl.edu
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| Organization name |
Washington University School of Medicine
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| Department |
Genetics
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| Lab |
GTAC Lab
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| Street address |
660 S. Euclid Ave.
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| City |
St. Louis |
| State/province |
MO |
| ZIP/Postal code |
63110 |
| Country |
USA |
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| Platforms (1) |
| GPL10904 |
Illumina HumanHT-12 V4.0 expression beadchip (gene symbol) |
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| Samples (24)
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| Relations |
| BioProject |
PRJNA296003 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE73046_non-normalized.txt.gz |
4.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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