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Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process

Oncogene volume 35, pages 1099–1110 (2016)Cite this article

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Abstract

Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process uses complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42 or Dyn2. Rather, inhibition of Dyn2 causes a marked upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization and regulated by disparate molecular mechanisms.

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Acknowledgements

This work was supported by R01 CA104125 to MAM, P30DK084567 (Mayo Clinic Center for Cell Signaling in Gastroenterology), T32 DK007198 (to RDE), and P50 CA102701 (Mayo Clinic SPORE in Pancreatic Cancer, to GLR).

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Author notes

  1. R D Eppinga

    Present address: 4Current Address: Department of Biology, Dordt College, Sioux Center, IA, USA.,

  2. H Cao, R D Eppinga and G L Razidlo: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA

    H Cao, R D Eppinga, G L Razidlo, E W Krueger, J Chen & M A McNiven

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA

    H Cao, G L Razidlo, L Qiang & M A McNiven

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  1. H Cao
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  7. M A McNiven
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Correspondence to M A McNiven.

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Cao, H., Eppinga, R., Razidlo, G. et al. Stromal fibroblasts facilitate cancer cell invasion by a novel invadopodia-independent matrix degradation process. Oncogene 35, 1099–1110 (2016). https://doi.org/10.1038/onc.2015.163

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