Nature Cancer: Let cancer cells "stay awake"!

Recently, a research team from the Icahn School of Medicine at Mount Sinai in the United States came up with an idea: to permanently stay in the dormant phase of tumor cells (that is, the cell cycle is arrested in the G0/G1 phase), and have been "sleeping"! The study, recently published in Nature Cancer, elucidates the critical role of the extracellular matrix in the tumor microenvironment for tumor cells to enter and maintain a dormant state
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Research results (Source: Nature Cancer)

First, the researchers started with the three-dimensional organization of the collagen extracellular matrix (ECM), the "home ground" of dormant tumor cells
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Under multiphoton second-harmonic imaging, the results showed that collagen fibers surrounding dormant cells are characterized by nonlinear arrangement and wave-like structure, and can switch to a highly linear state during cancer cell reactivation
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Dormant tumor cells and proliferating tumor cells (Source: Nature Cancer)

Since the ECM of dormant and proliferating tumors is structurally different, the investigators sought to determine whether the composition or "matrix body" of decellularized proliferating and dormant tumors by mass spectrometry different
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Comparison of collagen types between T-HEp3 (proliferating tumor) and D-HEp3 (dormant tumor) (Image source: Nature Cancer)

Next, the researchers used a human-mouse xenograft system to further determine the relative contribution of tumor cells (human protein sequences) and stromal cells (mouse protein sequences) to matrix body production
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Comparison of the density of various types of collagen (Source: Nature Cancer)

Could a bioengineered scaffold of type II collagen treat locally residual cancer cells (as observed after primary tumor resection) prevent residual dormant cancer cells from being awakened? To this end, the study used T-HEp3 expressing the CDK2 biosensor Cells, the final results showed that only 20 percent of mice treated with scaffolded type III collagen relapsed after tumor surgery, compared with 80 percent of tumors in the control group
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 Local tumor recurrence after surgery (Source: Nature Cancer)

As the increased abundance of type III collagen correlates with high expression of COL3A1 (part of a gene network that operates during dormancy in cancer cells) at the mRNA and protein levels
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Finally, the researchers discovered a positive feedback pathway between collagen type III and dormant tumor cells: collagen type III binds to the tumor cell DDR1 receptor, activating STAT1 (a potential transcription factor downstream of DDR1 that regulates dormancy) into the nucleus The expression of COL3A1 is promoted, and then the tumor cells secrete type III collagen, which in turn maintains the tumor cells in a dormant state
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Positive feedback pathway between type III collagen and dormant tumor cells (Credit: Nature Cancer)

Overall, this study describes a novel mechanism of cell dormancy: the addition of type III collagen to the tumor microenvironment can promote tumor cells to enter and maintain a dormant state, inhibiting tumor proliferation
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[1] Di Martino, JS, Nobre, AR, Mondal, C.

[2] Sosa MS, Bragado P, Aguirre-Ghiso JA.

[3] New breakthrough in tumor! Nature Cancer: This collagen can make tumor cells go dormant! https://mp.