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- aggregation classification "A1".
- aggregation creator B678728.
- aggregation creator B678729.
- aggregation creator B678730.
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- aggregation date "2013".
- aggregation format "application/pdf".
- aggregation hasFormat 4232451.bibtex.
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- aggregation isPartOf urn:issn:1465-5411.
- aggregation language "eng".
- aggregation rights "I have retained and own the full copyright for this publication".
- aggregation subject "Medicine and Health Sciences".
- aggregation title "A nanobody targeting the F-actin capping protein CapG restrains breast cancer metastasis".
- aggregation abstract "Introduction: Aberrant turnover of the actin cytoskeleton is intimately associated with cancer cell migration and invasion. Frequently however, evidence is circumstantial, and a reliable assessment of the therapeutic significance of a gene product is offset by lack of inhibitors that target biologic properties of a protein, as most conventional drugs do, instead of the corresponding gene. Proteomic studies have demonstrated overexpression of CapG, a constituent of the actin cytoskeleton, in breast cancer. Indirect evidence suggests that CapG is involved in tumor cell dissemination and metastasis. In this study, we used llama-derived CapG single-domain antibodies or nanobodies in a breast cancer metastasis model to address whether inhibition of CapG activity holds therapeutic merit. Methods: We raised single-domain antibodies (nanobodies) against human CapG and used these as intrabodies (immunomodulation) after lentiviral transduction of breast cancer cells. Functional characterization of nanobodies was performed to identify which biochemical properties of CapG are perturbed. Orthotopic and tail vein in vivo models of metastasis in nude mice were used to assess cancer cell spreading. Results: With G-actin and F-actin binding assays, we identified a CapG nanobody that binds with nanomolar affinity to the first CapG domain. Consequently, CapG interaction with actin monomers or actin filaments is blocked. Intracellular delocalization experiments demonstrated that the nanobody interacts with CapG in the cytoplasmic environment. Expression of the nanobody in breast cancer cells restrained cell migration and Matrigel invasion. Notably, the nanobody prevented formation of lung metastatic lesions in orthotopic xenograft and tail-vein models of metastasis in immunodeficient mice. We showed that CapG nanobodies can be delivered into cancer cells by using bacteria harboring a type III protein secretion system (T3SS). Conclusions: CapG inhibition strongly reduces breast cancer metastasis. A nanobody-based approach offers a fast track for gauging the therapeutic merit of drug targets. Mapping of the nanobody-CapG interface may provide a platform for rational design of pharmacologic compounds.".
- aggregation authorList BK1043150.
- aggregation issue "6".
- aggregation volume "15".
- aggregation aggregates 4236345.
- aggregation isDescribedBy 4232451.
- aggregation similarTo bcr3585.
- aggregation similarTo LU-4232451.