Transcriptome profiling of a TGF-β-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies
Open accessAbstract
Transforming growth factor (TGF)-beta plays a dual role in tumorigenesis, switching from acting as a growth inhibitory tumor suppressor early in the process, to a tumor promoter in late-stage disease. Since TGF-beta's prometastatic role may be linked to its ability to induce tumor cell epithelial-to-mesenchymal transition (EMT), we explored TGF-beta's EMT-promoting pathways by analysing the transcriptome changes occurring in BRI-JM01 mammary tumor epithelial cells undergoing a TGF-beta-induced EMT. We found the clusterin gene to be the most highly upregulated throughout most of the TGF-beta time course, and showed that this results in an increase of the secreted form of clusterin. By monitoring several hallmark features of EMT, we demonstrated that antibodies targeting secreted clusterin inhibit the TGF-beta-induced EMT of BRI-JM01 cells, as well as the invasive phenotype of several other breast and prostate tumor cell lines (4T1, NMuMG, MDA-MB231LM2 and PC3), without affecting the proliferation of these cells. These results indicate that secreted clusterin is a functionally important EMT mediator that lies downstream within TGF-beta's EMT-promoting transcriptional cascade, but not within its growth-inhibitory pathways. To further investigate the role played by secreted clusterin in tumor metastasis, we assessed the effect of several anti-clusterin monoclonal antibodies in vivo using a 4T1 syngeneic mouse breast cancer model and found that these antibodies significantly reduce lung metastasis. Taken together, our results reveal a role for secreted clusterin as an important extracellular promoter of EMT, and suggest that antibodies targeting clusterin may inhibit tumor metastasis without reducing the beneficial growth inhibitory effects of TGF-beta.
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In other in vitro systems, TGFβ promotes axonal outgrowth of injured neurons and blockade of TGFβRII alters neuronal polarity and leads to shorter axons.
“In other in vitro systems, TGFβ promotes axonal outgrowth of injured neurons21,22,39,40 and blockade of TGFβRII alters neuronal polarity and leads to shorter axons42.”
From GDF10 is a signal for axonal sprouting and functional recovery after stroke (2015) · cites this paper as [42]
The Introduction describes TGF-β signaling, and the section on BRI-JM01 cells examines epithelial-to-mesenchymal transition in a mammary tumor cell line. Searches for injured neurons, axonal outgrowth, neuronal polarity, and TGF-βRII blockade found no passage addressing either neuronal claim; the cited paper cannot verify them. (LLM, conf=0.77)
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- Authors
- Lenferink, A. E. G., Cantin, C., Nantel, A., Wang, E., Durocher, Y., Banville, M., Paul-Roc, B., Marcil, A., Wilson, M. R., & O'Connor-McCourt, M. D.
- Affiliations
- Biotechnology Research Institute (CA)
- University of Wollongong (AU)
- Corresponding author
- Lenferink, A E G
- Venue
- Oncogene
- Published
- 2009-11-23
- Volume
- 29
- Issue
- 6
- Pages
- 831-844
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2079135826
- Cited by
- 81
- References
- 89
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 5 · 2019: 5 · 2018: 2 · 2017: 8 · 2016: 4 · 2015: 7 · 2014: 11 · 2013: 8 · 2012: 10
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- NPARC (submittedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Funders
- University Health Network
- Topics
- Health Sciences › Medicine › Oncology › Clusterin in disease pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- TGF-beta, epithelial-mesenchymal transition, metastasis, breast cancer, prostate cancer, lung metastasis, tumor invasion
- MeSH terms
- Animals, Antibodies, Antibodies, Monoclonal, Breast Neoplasms, Cell Movement, Epithelial Cells, Extracellular Space, Female, Humans, Immunoglobulin G, Lung Neoplasms, Mesoderm, Mice, Inbred BALB C, Phenotype, RNA, Messenger, Transcription, Genetic, Reproducibility of Results, Transforming Growth Factor beta, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Cell Line, Tumor, Cell Proliferation, Clusterin, Mice
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