Cargando…

Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody

The successful application of antibody-based therapeutics in either primary or metastatic cancer depends upon the selection of rare cell surface epitopes that distinguish cancer cells from surrounding normal epithelial cells. By contrast, as circulating tumor cells (CTCs) transit through the bloodst...

Descripción completa

Detalles Bibliográficos
Autores principales: Micalizzi, Douglas S., Che, Dante, Nicholson, Benjamin T., Edd, Jon F., Desai, Niyati, Lang, Evan R., Toner, Mehmet, Maheswaran, Shyamala, Ting, David T., Haber, Daniel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618049/
https://www.ncbi.nlm.nih.gov/pubmed/36256815
http://dx.doi.org/10.1073/pnas.2209563119
_version_ 1784820968226553856
author Micalizzi, Douglas S.
Che, Dante
Nicholson, Benjamin T.
Edd, Jon F.
Desai, Niyati
Lang, Evan R.
Toner, Mehmet
Maheswaran, Shyamala
Ting, David T.
Haber, Daniel A.
author_facet Micalizzi, Douglas S.
Che, Dante
Nicholson, Benjamin T.
Edd, Jon F.
Desai, Niyati
Lang, Evan R.
Toner, Mehmet
Maheswaran, Shyamala
Ting, David T.
Haber, Daniel A.
author_sort Micalizzi, Douglas S.
collection PubMed
description The successful application of antibody-based therapeutics in either primary or metastatic cancer depends upon the selection of rare cell surface epitopes that distinguish cancer cells from surrounding normal epithelial cells. By contrast, as circulating tumor cells (CTCs) transit through the bloodstream, they are surrounded by hematopoietic cells with dramatically distinct cell surface proteins, greatly expanding the number of targetable epitopes. Here, we show that an antibody (23C6) against cadherin proteins effectively suppresses blood-borne metastasis in mouse isogenic and xenograft models of triple negative breast and pancreatic cancers. The 23C6 antibody is remarkable in that it recognizes both the epithelial E-cadherin (CDH1) and mesenchymal OB-cadherin (CDH11), thus overcoming considerable heterogeneity across tumor cells. Despite its efficacy against single cells in circulation, the antibody does not suppress primary tumor formation, nor does it elicit detectable toxicity in normal epithelial organs, where cadherins may be engaged within intercellular junctions and hence inaccessible for antibody binding. Antibody-mediated suppression of metastasis is comparable in matched immunocompetent and immunodeficient mouse models. Together, these studies raise the possibility of antibody targeting CTCs within the vasculature, thereby suppressing blood-borne metastasis.
format Online
Article
Text
id pubmed-9618049
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher National Academy of Sciences
record_format MEDLINE/PubMed
spelling pubmed-96180492022-10-31 Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody Micalizzi, Douglas S. Che, Dante Nicholson, Benjamin T. Edd, Jon F. Desai, Niyati Lang, Evan R. Toner, Mehmet Maheswaran, Shyamala Ting, David T. Haber, Daniel A. Proc Natl Acad Sci U S A Biological Sciences The successful application of antibody-based therapeutics in either primary or metastatic cancer depends upon the selection of rare cell surface epitopes that distinguish cancer cells from surrounding normal epithelial cells. By contrast, as circulating tumor cells (CTCs) transit through the bloodstream, they are surrounded by hematopoietic cells with dramatically distinct cell surface proteins, greatly expanding the number of targetable epitopes. Here, we show that an antibody (23C6) against cadherin proteins effectively suppresses blood-borne metastasis in mouse isogenic and xenograft models of triple negative breast and pancreatic cancers. The 23C6 antibody is remarkable in that it recognizes both the epithelial E-cadherin (CDH1) and mesenchymal OB-cadherin (CDH11), thus overcoming considerable heterogeneity across tumor cells. Despite its efficacy against single cells in circulation, the antibody does not suppress primary tumor formation, nor does it elicit detectable toxicity in normal epithelial organs, where cadherins may be engaged within intercellular junctions and hence inaccessible for antibody binding. Antibody-mediated suppression of metastasis is comparable in matched immunocompetent and immunodeficient mouse models. Together, these studies raise the possibility of antibody targeting CTCs within the vasculature, thereby suppressing blood-borne metastasis. National Academy of Sciences 2022-10-18 2022-10-25 /pmc/articles/PMC9618049/ /pubmed/36256815 http://dx.doi.org/10.1073/pnas.2209563119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Micalizzi, Douglas S.
Che, Dante
Nicholson, Benjamin T.
Edd, Jon F.
Desai, Niyati
Lang, Evan R.
Toner, Mehmet
Maheswaran, Shyamala
Ting, David T.
Haber, Daniel A.
Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title_full Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title_fullStr Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title_full_unstemmed Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title_short Targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
title_sort targeting breast and pancreatic cancer metastasis using a dual-cadherin antibody
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618049/
https://www.ncbi.nlm.nih.gov/pubmed/36256815
http://dx.doi.org/10.1073/pnas.2209563119
work_keys_str_mv AT micalizzidouglass targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT chedante targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT nicholsonbenjamint targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT eddjonf targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT desainiyati targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT langevanr targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT tonermehmet targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT maheswaranshyamala targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT tingdavidt targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody
AT haberdaniela targetingbreastandpancreaticcancermetastasisusingadualcadherinantibody