Researchers Discover How Cancer Cells Remain Dormant for Years Before Metastasis Occurs

Jose Javier Bravo Cordero

Jose Javier Bravo-Cordero microscopy research. Credit: Bravo-Cordero / Annenberg

Cells secrete type of collagen to stay dormant and wake up when collagen levels decrease.

Mount Sinai researchers have solved a major mystery in cancer research: How cancer cells remain dormant for years after they leave a tumor and travel to other parts of the body, before awakening to create metastatic cancer.

According to findings reported in Nature Cancer in December, the cells remain quiet by secreting a type of collagen, called type III collagen, in the environment around themselves, and only turn malignant once the level of collagen tapers off. The researchers found that by enriching the environment around the cells with this collagen, they could force the cells to remain in a dormant state and prevent tumor recurrence.

Tumor Cells in Collagen I Matrix Actively Proliferating

Tumor cells in a Collagen I matrix and cells are actively proliferating. In green we see the cell expressing a sensor to monitor cell cycle. Credit: Bravo-Cordero / Annenberg

“Our findings have potential clinical implications and may lead to a novel biomarker to predict tumor recurrences, as well as a therapeutic intervention to reduce local and distant relapses,” said senior author Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai. “This intervention aimed at preventing the awakening of dormant cells has been suggested as a therapeutic strategy to prevent metastatic outgrowth. As the biology of tumor dormancy gets uncovered and new specific drugs are developed, a combination of dormancy-inducing treatments with therapies that specifically target dormant cells will ultimately prevent local recurrence and metastasis and pave the way to cancer remission.”

Collagen III Triggers Dormancy

When cells are in Collagen III, the other type of collagen we found in our study, it triggers dormancy. Cells stop dividing and they remodel the matrix around them. Credit: Bravo-Cordero / Annenberg

Most cancer deaths are due to metastases, which can occur several years after a tumor is removed. Previous research has studied how dispersed tumor cells come out of dormancy; this new work showed how the cells remain dormant.

The study used high-resolution imaging techniques, including intravital two-photon microscopy, a technology that allows the visualization of dormant cells in their environment in real time in a living animal. This technology allowed the researchers to track dormant tumor cells in mouse models using breast and head and neck cancer cell lines. By using this technology, the researchers were able to visualize the changes in the architecture of the extracellular matrix as tumor cells became dormant and how it changed when these cells awoke.

In patient samples, the researchers showed that an abundance of the collagen could be used as a potential measurement to predict tumor recurrence and metastasis. In the mouse models, when scientists increased the amount of type III collagen around cancer cells that had left a tumor, cancer progression was interrupted and the disseminated cells were forced into a dormant state. Similar to wound treatment, in which collagen scaffolds have been proposed as a therapeutic alternative for complex skin wounds, this study suggests that by using strategies that aim to enrich the tumor microenvironment in type III collagen, metastasis may be prevented by activating tumor cell dormancy.

Reference: “A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy” by Julie S. Di Martino, Ana Rita Nobre, Chandrani Mondal, Isra Taha, Eduardo F. Farias, Elana J. Fertig, Alexandra Naba, Julio A. Aguirre-Ghiso and Jose Javier Bravo-Cordero, 13 December 2021, Nature Cancer.
DOI: 10.1038/s43018-021-00291-9

Funding was provided by the National Cancer Institute, The Tisch Cancer Institute, and the Susan G. Komen Foundation.

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