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.