Laminin, MMP9 and Tumor Growth

In the second study, which was related to the role of laminin-111 in cell quiescence, Bissell and another group of collaborators examined laminin-111 in the context of matrix metalloproteinase-9 (MMP9), a zinc-dependent enzyme that plays a huge role in tissue function by virtue of its ability to cleave or degrade many of the ECM constituent proteins, including laminin-111.

“Organization into polarized three-dimensional tissue structures defines whether epithelial cells are normal or malignant,” Bissell says. “We have shown that when MMP9 degrades laminin-111 in the ECM, the tissue architecture of breast cells becomes lost and cell proliferation is initiated. This is the first demonstration of how the degradation of laminin-111 by MMP9 in a physiological context contributes to tumor progression.”

A paper detailing the results of this study has appeared in the journal Genes and Development. The paper is titled “Raf-induced MMP9 Disrupts Tissue Architecture of Human Breast Cells in Three-Dimensional Culture and is Necessary for Tumor Growth in vivo.” Co-authoring the paper with Bissell were Alain Beliveau, Joni Mott, Alvin Lo, Emily Chen, Antonius Koller, Paul Yaswen and John Muschler.

Using a model of human breast cancer where breast epithelial cells were grown in three-dimensional cultures of basement membrane, a thin layer of ECM material that envelops breast and other glandular tissue, Bissell and her co-authors found that not only did excessive MMP9 activity disrupt tissue architecture, but that silencing MMP9 restored tissue architecture and decreased the ability of human beast cancer cells to form tumors in mice.

“We found that in all conditions where tumor cells could be reverted to a normal phenotype in our 3D assays, a novel signaling loop through a pathway of Raf/MEK/ERK proteins was responsible for MMP9 activity in the breast tumor cells,” says co-author Joni Mott, a researcher with Bissell’s group in Berkeley Lab’s Life Sciences Division. “Once MMP9 was activated, the proteinase targeted the destruction of laminin-111 within the basement membrane.”

Laminin-111 in the basement membrane, Mott explains, allows mammary epithelial cells to establish a normal polarized structural unit called an “acinus,” which is responsible for storing milk and making it available for babies when they suckle.

In their Genes and Development paper, Bissell, Mott and their co-authors reported that when the integrity of the tissue architecture was compromised by laminin proteolysis, the basement membrane no longer provided the appropriate signals to restrain epithelial cell proliferation. The result was a sustained signaling of the Raf/MEK/ERK pathway that leads to continued MMP9 production and further disruption of tissue architecture and loss of cell growth control.

“This work is particularly poignant because it provides potential new therapeutic targets for controlling breast cancer and revitalizes the possibility of targeting MMPs in cancer therapy,” Bissell says. “New information on how MMP9 and other MMPs truly function may provide highly targeted and effective therapeutic strategies to control MMP activity in cancer, and may soon lead to the development of novel cancer treatments.”

Both studies were funded in part by grants from the U.S. Department of Energy’s Office of Science, the National Cancer Institute, and the U.S. Department of Defense.

Lawrence Berkeley National Laboratory is a U.S. Department of Energy (DOE) national laboratory managed by the University of California for the DOE Office of Science. Berkeley Lab provides solutions to the world’s most urgent scientific challenges including sustainable energy, climate change, human health, and a better understanding of matter and force in the universe. It is a world leader in improving our lives through team science, advanced computing, and innovative technology.

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Lynn Yarris (510)486-5375 .(JavaScript must be enabled to view this email address)

A U.S. Department of Energy National Laboratory Operated by the University of California