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Role of Type III TGF-β Receptor Shedding in Regulating Tumorigenesis

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Date
2019
Author
Huang, Jennifer J.
Advisor
Blobe, Gerard C.
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Abstract

The type III TGF-β receptor (TβRIII) is a TGF-β co-receptor that presents ligand to the type II TGF-β receptor to initiate signaling. TβRIII also undergoes ectodomain shedding to release a soluble form (sTβRIII) that can bind ligand, sequestering it away from cell surface receptors. We have previously identified a TβRIII extracellular mutant that has enhanced ectodomain shedding (“super shedding (SS)” – TβRIII-SS). Here we utilize TβRIII-SS to study the balance of cell surface and soluble TβRIII in the context of lung cancer. We demonstrate that expressing TβRIII-SS in lung cancer cell models induces epithelial-mesenchymal transition (EMT) and that these TβRIII-SS (EMT) cells are less migratory, invasive and adhesive and more resistance to gemcitabine. Moreover, TβRIII-SS (EMT) cells exhibit decreased tumorigenicity but increased tumor growth in vitro and in vivo. These studies suggest that the balance of cell surface and soluble TβRIII may regulate a dichotomous role for TβRIII during cancer progression.

We have also demonstrated that cathepsin G and neutrophil elastase, proteases stored in the azurophil granules of neutrophils, can induce cleavage of cell surface TβRIII though no functional sTβRIII was detected. Similarly, activated neutrophils could induce TβRIII shedding on cancer cells. Interestingly, neutrophils generate sTβRIII that is resistant to shedding. These studies suggest that neutrophils may modulate the balance of cell surface and soluble TβRIII in the tumor microenvironment.

Description
Dissertation
Type
Dissertation
Department
Pharmacology
Subject
Molecular biology
Cellular biology
Oncology
ectodomain shedding
epithelial-to-mesenchymal transition
lung cancer
TGF-beta
type III TGF-beta receptor
Permalink
https://hdl.handle.net/10161/18645
Citation
Huang, Jennifer J. (2019). Role of Type III TGF-β Receptor Shedding in Regulating Tumorigenesis. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18645.
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