Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis
| Autor: | Audrey Brenot, Maria Clarke, Patrick Pence, Priscilla Y. Hwang, Craig E. Barcus, Gregory D. Longmore, Vasilios Morikis |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Stromal cell
medicine.drug_class Breast Neoplasms Tyrosine-kinase inhibitor Receptor tyrosine kinase Metastasis Mice Discoidin Domain Receptor 2 Collective Cell Migration Cancer-Associated Fibroblasts Paracrine actions Cell Movement Tumor Microenvironment medicine DDR2 Animals Humans Phosphorylation Tyrosine Kinase independent Tumor microenvironment biology Cell Biology Cell Biology and Disease Fibroblasts medicine.disease Metastatic breast cancer biology.protein Cancer research Female Tyrosine kinase Research Article |
| Zdroj: | Journal of Cell Science article-version (VoR) Version of Record |
| ISSN: | 1477-9137 0021-9533 |
| DOI: | 10.1242/jcs.258431 |
| Popis: | Both tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity has been hypothesized to be required for the metastatic activity of DDR2; however, inhibition of DDR2 tyrosine kinase activity, along with that of other RTKs, has failed to provide clinically relevant responses in metastatic patients. Here, we show that tyrosine kinase activity-independent action of DDR2 in tumor cells can support Matrigel invasion and in vivo metastasis. Paracrine actions of DDR2 in tumor cells and cancer-associated fibroblasts (CAFs) also support tumor invasion, migration and lung colonization in vivo. These data suggest that tyrosine kinase-independent functions of DDR2 could explain failures of tyrosine kinase inhibitor treatment in metastatic breast cancer patients and highlight the need for alternative therapeutic strategies that inhibit both tyrosine kinase-dependent and -independent actions of RTKs in the treatment of breast cancer. This article has an associated First Person interview with the first author of the paper. Summary: The collagen receptor DDR2, a receptor tyrosine kinase, exhibits tyrosine kinase-independent functions that influence paracrine regulation of breast tumor cell invasion and breast cancer metastasis. |
| Databáze: | OpenAIRE |
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