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Lack of Telopeptides in Fibrillar Collagen I Promotes the Invasion of a Metastatic Breast Tumor Cell Line

¹ Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts; ² Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, Massachusetts; and ³ Department of Thoracic Surgery, University Hospital of Lausanne (Centre Hospitalier Universitaire Vaudois), Lausanne, Switzerland

Requests for reprints: Yves Boucher, Department of Radiation Oncology, COX-7, Massachusetts General Hospital, 100 Blossom Street, Boston, MA 02114. Phone: 617-726-4082; Fax: 617-726-3603; E-mail: yves{at}steele.mgh.harvard.edu.

Defective fibrillar collagen polymerization in primary tumors has been correlated with increased metastasis. However, it is unclear how collagen organization influences tumor invasion. In this study, we show that collagen I polymerized without telopeptides (the flanking regions of collagen molecules) can differentially affect the three-dimensional migration of mammary carcinoma cells. MDA-MB-231 cells capable of proteolytic degradation and mesenchymal motion, invaded telopeptide-intact and telopeptide-free collagen gels to the same extent. In contrast, MDA-MB-435S cells, with typical features of amoeboid cells (poor collagenolytic activity, rounded cell morphology), were 5-fold more invasive in telopeptide-free than telopeptide-intact collagen. A fraction of the MDA-MB-435S cells that invaded telopeptide-intact or telopeptide-free collagen had a rounded morphology; however, in telopeptide-free collagen, a significant fraction of the cells switched from a rounded to elongated morphology (protrusion formation). The dynamic changes in cellular shape facilitated MDA-MB-435S locomotion through the narrow interfiber gaps, which were smaller than cell diameters. Based on the spherical morphology of MDA-MB-435S cells, we tested if the changes in cell shape and invasion were related to RhoA-ROCK activity; GTP-bound RhoA was measured in pull-down assays. RhoA activity was 1.8-fold higher for MDA-MB-435S cells seeded on telopeptide-free than telopeptide-intact collagen. Y27632 inhibition of ROCK, a Rho effector, significantly reduced the changes in cellular morphodynamics and the invasion of MDA-MB-435S cells but did not alter the invasion of MDA-MB-231 cells. Thus, the higher RhoA activity of MDA-MB-435S cells in telopeptide-free collagen enhances the changes in cellular morphodynamics associated with motility and invasion.

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