Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

Brian A. Aguado, Jordan R. Caffe, Dhaval Nanavati, Shreyas S. Rao, Grace G. Bushnell, Samira M. Azarin, Lonnie D. Shea

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM-coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche. Statement of Significance The pre-metastatic niche consists partially of ECM proteins that promote metastatic cell colonization to a target organ. We present a biomaterials-based approach to mimic this niche and identify ECM mediators of colonization. Using murine breast cancer models, we implanted microporous PCL scaffolds to recruit colonizing tumor cells in vivo. As a strategy to modulate colonization, we coated scaffolds with various ECM proteins, including decellularized lung and liver matrix from tumor-bearing mice. After characterizing the organ matrices using proteomics, myeloperoxidase was identified as an ECM protein contributing to colonization and validated using our scaffold. Our scaffold provides a platform to identify novel contributors to colonization and allows for the capture of colonizing tumor cells for a variety of downstream clinical applications.

Original languageEnglish (US)
Pages (from-to)13-24
Number of pages12
JournalActa Biomaterialia
Volume33
DOIs
StatePublished - Mar 15 2016

Bibliographical note

Funding Information:
We thank Dr. Jason Wertheim and Dr. Joseph Uzarski at Northwestern University for insightful conversations and advice on decellularization techniques. We also thank Matt Bury for providing antibodies for ECM immunofluorescence stains and Dr. Ji Yi for his assistance with SEM imaging, both at Northwestern University. We thank Katie Aguado for illustrating the mouse image in our graphical abstract. The Tumor Biology Core at Northwestern University provided LM2-4 cells for the study. The National Institutes of Health ( R01CA173745 ) and the Northwestern H Foundation Cancer Research Award supported this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the H Foundation. B.A.A. and G.G.B. are recipients of National Science Foundation Graduate Research Fellowships. The Northwestern Flow Cytometry Facility and a Cancer Center Support Grant ( NCI CA060553 ) supported flow cytometry work. The Northwestern University Proteomics Core Facility supported secretomics work and analysis. The Simpson Querrey Institute Equipment Core provided access and support to the Cytation3 and microscopy equipment.

Funding Information:
We thank Dr. Jason Wertheim and Dr. Joseph Uzarski at Northwestern University for insightful conversations and advice on decellularization techniques. We also thank Matt Bury for providing antibodies for ECM immunofluorescence stains and Dr. Ji Yi for his assistance with SEM imaging, both at Northwestern University. We thank Katie Aguado for illustrating the mouse image in our graphical abstract. The Tumor Biology Core at Northwestern University provided LM2-4 cells for the study. The National Institutes of Health (R01CA173745) and the Northwestern H Foundation Cancer Research Award supported this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the H Foundation. B.A.A. and G.G.B. are recipients of National Science Foundation Graduate Research Fellowships. The Northwestern Flow Cytometry Facility and a Cancer Center Support Grant (NCI CA060553) supported flow cytometry work. The Northwestern University Proteomics Core Facility supported secretomics work and analysis. The Simpson Querrey Institute Equipment Core provided access and support to the Cytation3 and microscopy equipment.

Keywords

  • Colonization
  • Extracellular matrix
  • Metastasis
  • Organ decellularization
  • Pre-metastatic niche

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