Abstract
Cancer cells disseminate and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Here we studied how disseminated tumor cells (DTCs) sense and remodel the extracellular matrix (ECM) to sustain dormancy. ECM proteomics revealed that dormant cancer cells assemble type III collagen-enriched ECM niche. Tumor-derived type III collagen is required to sustain tumor dormancy as its disruption restores tumor cell proliferation through DDR1-mediated STAT1 signaling. Second harmonic generation two-photon microscopy further revealed that the dormancy-to-reactivation transition is accompanied by changes in type III collagen architecture and abundance. Analysis of clinical samples revealed that 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. Our data supports that the manipulation of these mechanisms could serve as a barrier to metastasis through DTCs dormancy induction.
Highlights
The majority of cancer deaths are due to metastasis[1]
Our work describes a new mechanism of cellular dormancy, by which the assembly by cancer cells of a pro-quiescent extracellular matrix (ECM) enriched in type III collagen could potentially be exploited to prevent tumor recurrences and metastasis
We explored the concept of dormancy niches further and incorporate the idea that tumor cells themselves actively contribute to the assembly of pro-dormant ECM niches
Summary
The majority of cancer deaths are due to metastasis[1]. metastases can occur years or decades after primary tumor removal. Proteolysis of the ECM protein laminin-111 by the matrix metalloproteinase MMP9 secreted by neutrophils, was shown to interrupt dormancy and drive metastasis outgrowth through integrin a3b125, suggesting that remodeling of the ECM microenvironment can activate metastatic growth after dormancy These studies point towards a role for the ECM and ECM remodeling as drivers of reactivation of growth from dormancy, little attention has been paid to the role of tumor cell-derived ECM and its role in dormancy. Our studies demonstrate the potential therapeutic use of type III collagen to prevent the reawakening of cancer cells by inducing and maintaining cancer cell dormancy They illustrate a way by which therapeutic targeting of pro-metastatic ECM by correcting its composition to a prodormancy role can lead to prevention of local recurrence or metastatic outgrowth
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