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Increased type III TGF-? receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition.

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

SUBMITTER: Huang JJ

PROVIDER: S-EPMC6586422 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition.

Huang Jennifer J JJ Corona Armando L AL Dunn Brian P BP Cai Elise M EM Prakken Jesse N JN Blobe Gerard C GC

Oncogene 20190114 18

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 ...[more]

PMID: 30643193

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Project description:DCLK1 and Lgr5 have recently been identified as markers of quiescent and cycling stem cells in the small intestinal crypts, respectively. Epithelial-mesenchymal transition (EMT) is a key development program that is often activated during cancer invasion and metastasis, and also imparts a self-renewal capability to disseminating cancer cells. Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we observed a relative decrease in DCLK1 expression in the colonic crypts, with significant shift towards stromal staining at peak (12 days post infection) hyperplasia, whereas staining for Lgr5 and Msi-1 increased several fold. When hyperplasia was regressing (days 20-34), an expansion of DCLK1+ve cells in the CR-infected crypts compared with that seen in uninfected control was recorded. Purified colonic crypt cells exhibiting epigenetic modulation of the transforming growth factor-? (TGF?), Wnt and Notch pathways on 12 or 34 days post infection formed monolayers in vitro, and underwent trans-differentiation into fibroblast-like cells that stained positive for vimentin, fibronectin and DCLK1. These cells when trypsinized and regrown in soft agar, formed colonospheres/organoids that developed into crypt-like structures (colonoids) in Matrigel and stained positive for DCLK1. Mice exhibiting 12 or 34 days of TMCH were given azoxymethane once for 8?h (Gp1) or weekly for 3 weeks (Gp2), and subjected to crypt isolation. Crypt cells from Gp1 animals formed monolayers as well as colonospheres in soft agar and nodules/tumors in nude mice. Crypt cells isolated from Gp2 animals failed to form the monolayers, but developed into colonospheres in soft agar and nodules/tumors in nude mice. Thus, both hyperplasia and increased presence of DCLK1+ve cells promote cellular transformation in response to a second hit. The TMCH model, therefore, provides an excellent template to study how alterations in intestinal stem cells promote trans-differentiation, crypt regeneration or colon carcinogenesis following bacterial infection.

Dataset Information

Increased type III TGF-? receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition.

Publications

Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition.

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