PUBLICATION
Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2
- Authors
- Rogers, S., Zhang, C., Anagnostidis, V., Liddle, C., Fishel, M.L., Gielen, F., Scholpp, S.
- ID
- ZDB-PUB-231002-54
- Date
- 2023
- Source
- Proceedings of the National Academy of Sciences of the United States of America 120: e2217612120e2217612120 (Journal)
- Registered Authors
- Scholpp, Steffen
- Keywords
- Wnt/PCP signalling, cell migration, cytoneme, gastric cancer, morphogen
- MeSH Terms
-
- Animals
- Cancer-Associated Fibroblasts*
- Cell Line, Tumor
- Humans
- Stomach Neoplasms*/genetics
- Tumor Microenvironment
- Wnt Signaling Pathway
- Zebrafish
- PubMed
- 37722040 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Rogers, S., Zhang, C., Anagnostidis, V., Liddle, C., Fishel, M.L., Gielen, F., Scholpp, S. (2023) Cancer-associated fibroblasts influence Wnt/PCP signaling in gastric cancer cells by cytoneme-based dissemination of ROR2. Proceedings of the National Academy of Sciences of the United States of America. 120:e2217612120e2217612120.
Abstract
Cancer-associated fibroblasts (CAFs) are a crucial component in the tumor microenvironment influencing cancer progression. Besides shaping the extracellular matrix, these fibroblasts provide signaling factors to facilitate tumor survival and alter tumor behavior. In gastric cancer, one crucial signaling pathway influencing invasion and metastasis is the Wnt/Planar Cell Polarity (PCP) signaling. The crucial PCP ligand in this context is WNT5A, which is produced by the CAFs, and gastric cancer cells react upon this signal by enhanced polarized migration. Why gastric cancer cells respond to this signal is still unclear, as their expression level for the central WNT5A receptor, ROR2, is very low. Here, we show that CAFs display long and branched filopodia that form an extensive, complex network engulfing gastric cancer cells, such as the gastric cancer cell line AGS. CAFs have a significantly higher expression level of ROR2 than normal gastric fibroblasts and AGS cells. By high-resolution imaging, we observe a direct transfer of fluorescently tagged ROR2 from CAF to AGS cells by signaling filopodia, known as cytonemes. Surprisingly, we find that the transferred ROR2 complexes can activate Wnt/JNK signaling in AGS cells. Consistently, blockage of ROR2 function in the CAFs leads to reduced paracrine Wnt/JNK signaling, cell polarization, and migration of the receiving AGS cells. Complementary, enhanced migration via paracrine ROR2 transfer was observed in a zebrafish in vivo model. These findings demonstrate a fresh role for cytoneme-mediated signaling in the tumor microenvironment. Cytonemes convey Wnt receptors from CAFs to gastric cancer cells, allowing them to respond to Wnt/PCP signals.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
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