Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential

Verline Justilien, Roderick P. Regala, I. Chu Tseng, Michael P. Walsh, Jyotica Batra, Evette S Radisky, Nicole R Murray, Alan P Fields

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10 -/- mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells.

Original languageEnglish (US)
Article numbere35040
JournalPLoS One
Volume7
Issue number4
DOIs
StatePublished - Apr 24 2012

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stromelysin 2
Matrix Metalloproteinase 10
Neoplastic Stem Cells
lung neoplasms
Stem cells
stem cells
Tumors
Lung Neoplasms
oncospheres
Maintenance
neoplasms
Neoplasms
Gene expression
metastasis
Cells
mice
Stem Cells
Growth
neoplasm cells
gene expression

ASJC Scopus subject areas

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

Cite this

Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. / Justilien, Verline; Regala, Roderick P.; Tseng, I. Chu; Walsh, Michael P.; Batra, Jyotica; Radisky, Evette S; Murray, Nicole R; Fields, Alan P.

In: PLoS One, Vol. 7, No. 4, e35040, 24.04.2012.

Research output: Contribution to journalArticle

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