Li, Jiahui, Wu, Xiaolin, Schiffmann, Lars, MacVicar, Thomas, Zhou, Chenghui, Wang, Zhefang, Li, Dai, Camacho, Oscar Velazquez, Heuchel, Reiner, Odenthal, Margarete 
ORCID: 0000-0002-2424-0960, Hillmer, Axel, Quaas, Alexander, Zhao, Yue ORCID: 0000-0002-6790-3402, Bruns, Christiane J. and Popp, Felix C.
(2021).
IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth.
Cancers, 13 (21).
BASEL:
MDPI.
ISSN 2072-6694
Abstract
Simple Summary: Pancreatic cancer has the lowest survival rate of all malignancies. Understanding the interplay between tumor and stroma could lead to the development of new therapies. The metabolic role of interleukin 17B/interleukin 17B receptor (IL-17B/RB) has not been adequately studied in pancreatic cancer and is poorly understood. Here, we investigate the IL-17B/RB-mediated interactions between the tumor and the stroma. We analyze murine as well as human stromal and tumor cells, animal experiments with immunocompromised mice, and human cell lines with overexpression and knockdown of IL-17RB. We report that aberrant expression of IL-17B/RB in stromal pancreatic stellate cells (PSCs) accelerates tumor cell growth. IL-17B/RB-signaling supplies energy by increased oxidative phosphorylation (OXPHOS). Blocking IL-17B/RB to inhibit the tumor to stroma crosstalk could be a potential targeted therapy for pancreatic cancer.In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.
| Item Type: | Journal Article | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Creators: |
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| URN: | urn:nbn:de:hbz:38-591898 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| DOI: | 10.3390/cancers13215338 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Journal or Publication Title: | Cancers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Volume: | 13 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Number: | 21 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Date: | 2021 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Publisher: | MDPI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Place of Publication: | BASEL | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ISSN: | 2072-6694 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Language: | English | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Faculty: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Divisions: | Unspecified | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Subjects: | no entry | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| URI: | http://kups.ub.uni-koeln.de/id/eprint/59189 |
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