Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma

Brandi N. Baird, Mark J. Schliekelman, Young Ho Ahn, Yulong Chen, Jonathon D. Roybal, Bartley J. Gill, Dhruva K. Mishra, Baruch Erez, Michael O'Reilly, Yanan Yang, Mayuri Patel, Xin Liu, Nishan Thilaganathan, Irina V. Larina, Mary E. Dickinson, Jennifer L. West, Don L. Gibbons, Diane D. Liu, Min P. Kim, John M. HicksIgnacio I. Wistuba, Samir M. Hanash, Jonathan M. Kurie

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-of-function experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cell-derived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.

Original languageEnglish (US)
Article numbere67054
JournalPloS one
Volume8
Issue number6
DOIs
StatePublished - Jun 10 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Baird, B. N., Schliekelman, M. J., Ahn, Y. H., Chen, Y., Roybal, J. D., Gill, B. J., Mishra, D. K., Erez, B., O'Reilly, M., Yang, Y., Patel, M., Liu, X., Thilaganathan, N., Larina, I. V., Dickinson, M. E., West, J. L., Gibbons, D. L., Liu, D. D., Kim, M. P., ... Kurie, J. M. (2013). Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma. PloS one, 8(6), [e67054]. https://doi.org/10.1371/journal.pone.0067054