Abstract
Primary tumor (PT) immune cells and pre-metastatic niche (PMN) sites are critical to metastasis. Recently, synthetic biomaterial scaffolds used as PMN mimics are shown to capture both immune and metastatic tumor cells. Herein, studies are performed to investigate whether the scaffold-mediated redirection of immune and tumor cells would alter the primary tumor microenvironment (TME). Transcriptomic analysis of PT cells from scaffold-implanted and mock-surgery mice identifies differentially regulated pathways relevant to invasion and metastasis progression. Transcriptomic differences are hypothesized to result from scaffold-mediated modulations of immune cell trafficking and phenotype in the TME. Culturing tumor cells with conditioned media generated from PT immune cells of scaffold-implanted mice decrease invasion in vitro more than two-fold relative to mock surgery controls and reduce activity of invasion-promoting transcription factors. Secretomic characterization of the conditioned media delineates interactions between immune cells in the TME and tumor cells, showing an increase in the pan-metastasis inhibitor decorin and a concomitant decrease in invasion-promoting chemokine (C-C motif) ligand 2 (CCL2) in scaffold-implanted mice. Flow cytometric and transcriptomic profiling of PT immune cells identify phenotypically distinct tumor-associated macrophages (TAMs) in scaffold-implanted mice, which may contribute to an invasion-suppressive TME. Taken together, this study demonstrates biomaterial scaffolds systemically influence metastatic progression through manipulation of the TME.
| Original language | English (US) |
|---|---|
| Article number | 1700903 |
| Journal | Advanced Healthcare Materials |
| Volume | 7 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 23 2018 |
Funding
B.A.A. and R.M.H. contributed equally to this work. B.A.A., R.M.H, and L.D.S. designed the experiments; B.A.A., R.M.H., G.G.B., S.M.A., S.S.R, R.S.O., and Y.Z. performed experiments; B.A.A. and R.M.H. collected data, performed data analyses, and prepared figures; J.T.D. analyzed TRACER results; D.N. analyzed secretomics results; M.J.S. analyzed RNAseq results; J.S.J. edited and advised on the manuscript; B.A.A., R.M.H. and L.D.S. wrote and edited the manuscript. The Tumor Biology Core at Northwestern University provided MDA-MB-231BR and 4T1 cells for the study. The Northwestern University Proteomics Core Facility supported secretomics work and analysis. The Simpson Querrey Institute Equipment Core provided access to microscopy equipment. Flow cytometry work was supported by the Northwestern University Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core Facility and the University of Michigan Flow Cytometry Core. The authors thank Katie Aguado for illustrating the mouse image in the schematics. Financial support for this work was provided by the National Institutes of Health and the National Cancer Institute (R01 CA173745). B.A.A. and G.G.B. acknowledge the support of a National Science Foundation Graduate Research Fellowship.
Keywords
- biomaterial
- immunomodulation
- metastasis
- pre-metastatic niche
- tumor microenvironment
ASJC Scopus subject areas
- Biomaterials
- Biomedical Engineering
- Pharmaceutical Science