Browsing by Author "Emerson, Robert"

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    ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase
    (Elsevier, 2018-02-01) Tomar, Sunil; Plotnik, Joshua P.; Haley, James; Scantland, Joshua; Dasari, Subramanyam; Sheikh, Zahir; Emerson, Robert; Lenz, Dean; Hollenhorst, Peter C.; Mitra, Anirban K.; Pathology and Laboratory Medicine, School of Medicine
    Metastatic colonization involves paracrine/juxtacrine interactions with the microenvironment inducing an adaptive response through transcriptional regulation. However, the identities of transcription factors (TFs) induced by the metastatic microenvironment in ovarian cancer (OC) and their mechanism of action is poorly understood. Using an organotypic 3D culture model recapitulating the early events of metastasis, we identified ETS1 as the most upregulated member of the ETS family of TFs in metastasizing OC cells as they interacted with the microenvironment. ETS1 was regulated by p44/42 MAP kinase signaling activated in the OC cells interacting with mesothelial cells at the metastatic site. Human OC tumors had increased expression of ETS1, which predicted poor prognosis. ETS1 regulated OC metastasis both in vitro and in mouse xenografts. A combination of ChIP-seq and RNA-seq analysis and functional rescue experiments revealed FAK as the key transcriptional target and downstream effector of ETS1. Taken together, our results indicate that ETS1 is an essential transcription factor induced in OC cells by the microenvironment, which promotes metastatic colonization though the transcriptional upregulation of its target FAK.
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    Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer
    (American Association for Cancer Research, 2012-07) Shao, Minghai; Hollar, Stacy; Chambliss, Daphne; Schmitt, Jordan; Emerson, Robert; Chelladurai, Bhadrani; Perkins, Susan; Ivan, Mircea; Matei, Daniela; Department of Medicine, IU School of Medicine
    Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity.
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    Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression.
    (AACR, 2015-10-01) Lee, Jiyoon; Condello, Salvatore; Yakubov, Bakhtiyor; Emerson, Robert; Caperell-Grant, Andrea; Hitomi, Kiyotaka; Xie, Jingwu; Matei, Daniela; Department of Biochemistry and Molecular Biology, IU School of Medicine
    Purpose: Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca2+-dependent enzyme which crosslinks proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma. Experimental Design: Orthotopic pancreatic xenografts and co-culture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. Results: We show that TG2 secreted by cancer cells effectively molds the stroma by crosslinking collagen, which in turn activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells led to decreased size of pancreatic xenografts. Conclusions: Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the crosstalk between cancer cells and stroma fundamentally impacting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression.