Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression
Open accessAbstract
Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies.
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Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.
“These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
From Osteosarcoma (2022) · cites this paper as [217]
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- Authors
- Lizardo, M. M., Morrow, J. J., Miller, T. E., Hong, E. S., Ren, L., Mendoza, A., Halsey, C. H., Scacheri, P. C., Helman, L. J., & Khanna, C.
- Affiliations
- National Institutes of Health (US)
- Case Western Reserve University (US)
- Corresponding author
- Khanna, Chand
- ORCID
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 18
- Issue
- 11
- Pages
- 699-710
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC5094383
- OpenAlex
- W2539899796
- Cited by
- 50
- References
- 37
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 5 · 2019: 11 · 2018: 7 · 2017: 8 · 2016: 1
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Cancer Institute (F30CA183510, R01CA160356, F30CA186633, CA183510)
- National Institute of General Medical Sciences (T32GM007250)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- GRP78, lung metastasis, endoplasmic reticulum chaperone, osteosarcoma, mammary adenocarcinoma, anti-metastatic therapy, experimental metastasis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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