Cells that leave an original or ‘primary’ tumor can remain in a non-cancerous, ‘dormant’ state for years before awakening to generate tumors at other locations in the body—a stage in cancer progression called ‘metastatic cancer’.

Until now, we did not know how these traveling cells remained asleep for extended periods before waking again to reengage in creating havoc.

Researchers at Mount Sinai use proteomic analysis of the matrix surrounding the immigrant cells to show cells migrating away from primary tumor sites remain non-malignant by producing a common fibrous protein found in the extracellular matrix called type III collagen. It is only when these cells slow down or stop secreting this collagen into their surroundings that they turn malignant again.

Does that mean enveloping migrating cancerous cells with type III collagen could prevent them from turning cancerous? This study indicates, yes. The authors show scattered cancer cells remain in a dormant state preventing the recurrence of metastatic tumors if the environment of these cells is enriched with type III collagen.

“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 Jose Javier Bravo-Cordero, PhD, Associate Professor of Medicine (Hematology and Medical Oncology) at The Tisch Cancer Institute at Mount Sinai and senior author of the study.

The new findings are published in an article in the journal Nature Cancer on December 13, titled “A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.” Funding for the work came from the National Cancer Institute, The Tisch Cancer Institute, and the Susan G. Komen Foundation.

Earlier studies have investigated how scattered cancer cells reawaken from dormancy. The current study focuses on how these cells remain dormant. Specifically, the researchers investigate how disseminated tumor cells (DTCs) sense and remodel their surrounding extracellular matrix to remain dormant.

“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,” Bravo-Cordero said.

Metastasis—the spread of cancer to different organs by way of the lymphatic ducts or blood vessels—is a hallmark of advanced, stage four cancer. Most deaths due to cancer could potentially be prevented if the tumor remained localized at a single site. This would offer better odds of success for both chemotherapy and surgery in eliminating the tumor for good.

However, even years after a primary tumor has been removed, secondary tumors can occur due to the reawakening of dormant cells that had migrated away from the original tumor site before it was removed.

In this study, the researchers use high-resolution imaging protocols, including intravital two-photon microscopy. This imaging technology lets researchers study cells in their environment in real time in a living animal. Using intravital two-photon microscopy the authors track dormant tumor cells in mouse models using breast and head and neck cancer cell lines. This allowed them to detect changes in the organization of the extracellular matrix as tumor cells remained dormant and when they regained malignancy.

Based on their analysis of clinical samples from patients, the researchers show that the abundance of type III collagen could also be used to predict tumor recurrence and metastasis. They show type III collagen levels were increased in tumors from lymph node-negative head and neck squamous cell carcinoma (HNSCC) patients compared to lymph node-positive patients, supporting the predictive value of the collagen measurement.

In mouse model studies, when the scientists increased the amount of type III collagen around cancer cells that had left a tumor, cancer progression stalled and the disseminated cells maintained a dormant state. The authors show removing type III collagen from the matrix surrounding these cells reinitiates their proliferation through the activation of STAT1 signaling.

Bravo-Cordero says, “We envision in the future, clinical interventions aimed to prevent the awakening of dormant cells as a therapeutic strategy to prevent metastatic outgrowth. One of them could be by enriching their environment in Collagen III.”

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