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Browsing by Author "Decker, Joseph T."

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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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    Synergistic effect of eribulin and CDK inhibition for the treatment of triple negative breast cancer
    (Impact Journals, 2017) Rao, Shreyas S.; Stoehr, Jenna; Dokic, Danijela; Wan, Lei; Decker, Joseph T.; Konopka, Kristine; Thomas, Alexandra L.; Wu, Jia; Kaklamani, Virginia G.; Shea, Lonnie D.; Jeruss, Jacqueline S.; University of Alabama Tuscaloosa; Northwestern University; University of Michigan; University of Texas Health Science Center at San Antonio
    Activation of CDK2 in triple negative breast cancer (TNBC) can contribute to non-canonical phosphorylation of a TGF beta signaling component, Smad3, promoting cell proliferation and migration. Inhibition of CDK2 was shown to decrease breast cancer oncogenesis. Eribulin chemotherapy was used effectively in the treatment of TNBC. To this end, we tested therapeutic efficacy of a novel CDK2/9 inhibitor, CYC065, eribulin, and the combination of CYC065 and eribulin in 3 different TNBC cell lines, and an in vivo xenograft model. Specifically, we characterized cell proliferation, apoptosis, migration, cell cycle associated protein expression, treatment-related transcription factor activity, and tumor growth in TNBC. Treatment with CYC065 and eribulin in combination had a superior effect on decreasing cell proliferation, inducing apoptosis, and inhibiting migration in TNBC cell lines in vitro. Combination therapy inhibited non-canonical Smad3 phosphorylation at the T179 site in the protein linker region, and resulted in increased p15 and decreased c-myc expression. In a transcription factor array, combination treatment significantly increased activity of AP1 and decreased activity of factors including NF kappa B, SP1, E2F, and SMAD3. In an in vivo xenograft model of TNBC, individual and combination treatments resulted in a decrease in both tumor volume and mitotic indices. Taken together, these studies highlight the potential of this novel drug combination, CYC065 and eribulin, to suppress the growth of TNBC cells in vitro and in vivo, warranting further clinical investigation.