Browsing by Author "Bowser, Jessica L."

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    ADAM8 signaling drives neutrophil migration and ARDS severity
    (American Society for Clinical Investigation, 2022) Conrad, Catharina; Yildiz, Daniela; Cleary, Simon J.; Margraf, Andreas; Cook, Lena; Schlomann, Uwe; Panaretou, Barry; Bowser, Jessica L.; Karmouty-Quintana, Harry; Li, Jiwen; Berg, Nathaniel K.; Martin, Samuel C.; Aljohmani, Ahmad; Moussavi-Harami, S. Farshid; Wang, Kristin M.; Tian, Jennifer J.; Magnen, Mélia; Valet, Colin; Qiu, Longhui; Singer, Jonathan P.; Eltzschig, Holger K.; Bertrams, Wilhelm; Herold, Susanne; Suttorp, Norbert; Schmeck, Bernd; Ball, Zachary T.; Zarbock, Alexander; Looney, Mark R.; Bartsch, Jörg W.
    Acute respiratory distress syndrome (ARDS) results in catastrophic lung failure and has an urgent, unmet need for improved early recognition and therapeutic development. Neutrophil influx is a hallmark of ARDS and is associated with the release of tissue-destructive immune effectors, such as matrix metalloproteinases (MMPs) and membrane-anchored metalloproteinase disintegrins (ADAMs). Here, we observed using intravital microscopy that Adam8–/– mice had impaired neutrophil transmigration. In mouse pneumonia models, both genetic deletion and pharmacologic inhibition of ADAM8 attenuated neutrophil infiltration and lung injury while improving bacterial containment. Unexpectedly, the alterations of neutrophil function were not attributable to impaired proteolysis but resulted from reduced intracellular interactions of ADAM8 with the actin-based motor molecule Myosin1f that suppressed neutrophil motility. In 2 ARDS cohorts, we analyzed lung fluid proteolytic signatures and identified that ADAM8 activity was positively correlated with disease severity. We propose that in acute inflammatory lung diseases such as pneumonia and ARDS, ADAM8 inhibition might allow fine-tuning of neutrophil responses for therapeutic gain.
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    MUC1 stimulates EGFR expression and function in endometrial cancer
    (Impact Journals, LLC, 2016) Engel, Brian J.; Bowser, Jessica L.; Broaddus, Russell R.; Carson, Daniel D.
    The current standard of care for endometrial cancer patients involves hysterectomy with adjuvant radiation and chemotherapy, with no effective treatment for advanced and metastatic disease. MUC1 is a large, heavily glycosylated transmembrane protein that lubricates and protects cell surfaces and increases cellular signaling through the epidermal growth factor receptor (EGFR). We show for the first time that MUC1 stimulates EGFR expression and function in endometrial cancer. siRNA knockdown and CRISPR/Cas knockout of MUC1 reduced EGFR gene expression, mRNA, protein levels and signaling. MUC1 bound strongly to two regions of the EGFR promoter: -627/-511 and -172/-64. MUC1 knockout also reduced EGFR-dependent proliferation in two dimensional culture, as well as growth and survival in three dimensional spheroid cultures. MUC1 knockout cells were more sensitive to the EGFR inhibitor, lapatinib. Finally, MUC1 and EGFR co-expression was associated with increased cellular proliferation in human endometrial tumors. These data demonstrate the importance of MUC1-driven EGFR expression and signaling and suggest dual-targeted therapies may provide improved response for endometrial tumors.