Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

Maria E. Gonzalez; Emily E. Martin; Talha Anwar; Caroline Arellano-Garcia; Natasha Medhora; Arjun Lama; Yu Chih Chen; Kevin S. Tanager; Euisik Yoon; Kelley M. Kidwell; Chunxi Ge; Renny T. Franceschi; Celina G. Kleer

doi:10.1016/j.celrep.2016.12.079

Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

Maria E. Gonzalez, Emily E. Martin, Talha Anwar, Caroline Arellano-Garcia, Natasha Medhora, Arjun Lama, Yu Chih Chen, Kevin S. Tanager, Euisik Yoon, Kelley M. Kidwell, Chunxi Ge, Renny T. Franceschi, Celina G. Kleer

Yonsei Advanced Science Institute

Research output: Contribution to journal › Article › peer-review

80 Citations (Scopus)

Abstract

Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

Original language	English
Pages (from-to)	1215-1228
Number of pages	14
Journal	Cell Reports
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2016.12.079
Publication status	Published - 2017 Jan 31

Bibliographical note

Funding Information:
We thank members of the Kleer lab and Dr. Hernan Roca for discussions during the execution of this project, Dr. Gabriel Nunez for critical reading of the manuscript, and Dr. S. Takayama for guidance with the hanging drop spheroid assays. This work was supported by NIH grants (R01CA125577 and R01CA107469 to C.G.K.; F30CA196084 to T.A.; and R25GM086262 [PREP program,] to C.A-G.) and the University of Michigan Cancer Center support grant (P30CA046592).

Publisher Copyright:
© 2017 The Authors

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2016.12.079

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Gonzalez, M. E., Martin, E. E., Anwar, T., Arellano-Garcia, C., Medhora, N., Lama, A., Chen, Y. C., Tanager, K. S., Yoon, E., Kidwell, K. M., Ge, C., Franceschi, R. T., & Kleer, C. G. (2017). Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth. Cell Reports, 18(5), 1215-1228. https://doi.org/10.1016/j.celrep.2016.12.079

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abstract = "Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.",

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AU - Kleer, Celina G.

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N2 - Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

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Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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