Research and Publications - Department of Chemical & Biological Engineering

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Browsing Research and Publications - Department of Chemical & Biological Engineering by Author "Aguado, Brian A."

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    Biomaterial Scaffolds as Pre-metastatic Niche Mimics Systemically Alter the Primary Tumor and Tumor Microenvironment
    (Wiley, 2018) Aguado, Brian A.; Hartfield, Rachel M.; Bushnell, Grace G.; Decker, Joseph T.; Azarin, Samira M.; Nanavati, Dhaval; Schipma, Matthew J.; Rao, Shreyas S.; Oakes, Robert S.; Zhang, Yining; Jeruss, Jacqueline S.; Shea, Lonnie D.; Northwestern University; University of Michigan; University of Alabama Tuscaloosa
    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.
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    Engineering the pre-metastatic niche
    (Nature Portfolio, 2017) Aguado, Brian A.; Bushnell, Grace G.; Rao, Shreyas S.; Jeruss, Jacqueline S.; Shea, Lonnie D.; Northwestern University; University of Michigan; University of Alabama Tuscaloosa
    The pre-metastatic niche -the accumulation of aberrant immune cells and extracellular-matrix proteins in target organs primes the initially healthy organ microenvironment and renders it amenable for subsequent colonization by metastatic cancer cells. By attracting metastatic cells, mimics of the pre-metastatic niche offer both diagnostic and therapeutic potential. However, deconstructing the complexity of the niche by identifying the interactions between cell populations as well as the mediatory roles of the immune system, soluble factors, extracellular-matrix proteins and stromal cells has proved challenging. Experimental models are needed to recapitulate niche-population biology in situ and to mediate in vivo tumour-cell homing, colonization and proliferation. In this Review, we outline the biology of the pre-metastatic niche and discuss advances in the engineering of niche-mimicking biomaterials that regulate the behaviour of tumour cells at an implant site. Such 'oncomaterials' offer strategies for the early detection of metastatic events, the inhibition of the formation of the pre-metastatic niche and the attenuation of metastatic progression.
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    Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche
    (Elsevier, 2016) Aguado, Brian A.; Gaffe, Jordan R.; Nanavati, Dhaval; Rao, Shreyas S.; Bushnell, Grace G.; Azarin, Samira M.; Shea, Lonnie D.; Northwestern University; University of Alabama Tuscaloosa; University of Michigan; University of Minnesota Twin Cities
    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(epsilon-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. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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    Secretome identification of immune cell factors mediating metastatic cell homing
    (Nature Portfolio, 2015) Aguado, Brian A.; Wu, Jia J.; Azarin, Samira M.; Nanavati, Dhaval; Rao, Shreyas S.; Bushnell, Grace G.; Medicherla, Chaitanya B.; Shea, Lonnie D.; Northwestern University; University of Minnesota Twin Cities; University of Alabama Tuscaloosa; University of Michigan; Feinberg School of Medicine
    Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. MDA-MB-231 metastatic cell activity including cell invasion, migration, transendothelial migration, and proliferation were increased in D-SCM relative to control media. Our D-SCM secretome analysis yielded 144 secreted factor candidates that contribute to increased metastatic cell activity. The functional mediators of homing were identified using MetaCore software to determine interactions between the immune cell secretome and the TRACER-identified active transcription factors within metastatic cells. Among the 5 candidate homing factors identified, haptoglobin was selected and validated in vitro and in vivo as a key mediator of homing. Our studies demonstrate a novel systems biology approach to identify functional signaling factors associated with a cellular phenotype, which provides an enabling tool that complements large-scale protein identification provided by proteomics.