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  Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis

Elwakeel, E., Brueggemann, M., Wagih, J., Lityagina, O., Elewa, M. A. F., Han, Y., et al. (2022). Disruption of Prostaglandin E2 Signaling in Cancer-Associated Fibroblasts Limits Mammary Carcinoma Growth but Promotes Metastasis. CANCER RESEARCH, 82(7), 1380-1395. doi:10.1158/0008-5472.CAN-21-2116.

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Elwakeel, Eiman, Author
Brueggemann, Mirko, Author
Wagih, Jessica, Author
Lityagina, Olga, Author
Elewa, Mohammed A. F., Author
Han, Yingying, Author
Froemel, Timo, Author
Popp, Ruediger, Author
Nicolas, Adele M., Author
Schreiber, Yannick, Author
Gradhand, Elise, Author
Thomas, Dominique, Author
Nuesing, Rolf, Author
Steinmetz-Spaeh, Julia, Author
Savai, Rajkumar1, Author              
Fokas, Emmanouil, Author
Fleming, Ingrid, Author
Greten, Florian R., Author
Zarnack, Kathi, Author
Bruene, Bernhard, Author
Weigert, Andreas, Author more..
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

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 Abstract: The activation and differentiation of cancer-associated fibro-blasts (CAF) are involved in tumor progression. Here, we show that the tumor-promoting lipid mediator prostaglandin E2 (PGE(2)) plays a paradoxical role in CAF activation and tumor progression. Restricting PGE(2) signaling via knockout of microsomal prostaglandin E synthase-1 (mPGES-1) in PyMT mice or of the prostanoid E receptor 3 (EP3) in CAFs stunted mammary carcinoma growth associated with strong CAF proliferation. CAF proliferation upon EP3 inhibition required p38 MAPK signaling. Mechanistically, TGF beta-activated kinase-like protein (TAK1L), which was identified as a negative regulator of p38 MAPK activation, was decreased following ablation of mPGES-1 or EP3. In contrast with its effects on primary tumor growth, disruption of PGE2 signaling in CAFs induced epithelial-to-mesenchymal transition in cancer organoids and promoted metastasis in mice. Moreover, TAK1L expression in CAFs was associated with decreased CAF activation, reduced metastasis, and prolonged survival in human breast cancer. These data characterize a new pathway of regulating inflammatory CAF activation, which affects breast cancer progression. Significance: The inflammatory lipid prostaglandin E2 suppresses cancer-associated fibroblast expansion and activation to limit primary mammary tumor growth while promoting metastasis. [GRAPHICS]

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 Dates: 2022-04-01
 Publication Status: Published in print
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Title: CANCER RESEARCH
Source Genre: Journal
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Pages: - Volume / Issue: 82 (7) Sequence Number: - Start / End Page: 1380 - 1395 Identifier: ISSN: 0008-5472