Podocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy

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dc.contributor.authorSnyder, K.
dc.contributor.authorHughes, M.
dc.contributor.authorHedberg, B.
dc.contributor.authorBrandon, J.
dc.contributor.authorHernaez, D.
dc.contributor.authorBergqvist, P.
dc.contributor.authorCruz, F.
dc.contributor.authorPo, K.
dc.contributor.authorGraves, M.
dc.contributor.authorTurvey, M.
dc.contributor.authorNielsen, J.
dc.contributor.authorWilkins, J.
dc.contributor.authorMcColl, S.
dc.contributor.authorBabcook, J.
dc.contributor.authorRoskelley, C.
dc.contributor.authorMcNagny, K.
dc.date.issued2015
dc.description.abstractINTRODUCTION: Podocalyxin (gene name PODXL) is a CD34-related sialomucin implicated in the regulation of cell adhesion, migration and polarity. Upregulated expression of podocalyxin is linked to poor patient survival in epithelial cancers. However, it is not known if podocalyxin has a functional role in tumor progression. METHODS: We silenced podocalyxin expression in the aggressive basal-like human (MDA-MB-231) and mouse (4T1) breast cancer cell lines and also overexpressed podocalyxin in the more benign human breast cancer cell line, MCF7. We evaluated how podocalyxin affects tumorsphere formation in vitro and compared the ability of podocalyxin-deficient and podocalyxin-replete cell lines to form tumors and metastasize using xenogenic or syngeneic transplant models in mice. Finally, in an effort to develop therapeutic treatments for systemic cancers, we generated a series of antihuman podocalyxin antibodies and screened these for their ability to inhibit tumor progression in xenografted mice. RESULTS: Although deletion of podocalyxin does not alter gross cell morphology and growth under standard (adherent) culture conditions, expression of PODXL is required for efficient formation of tumorspheres in vitro. Correspondingly, silencing podocalyxin resulted in attenuated primary tumor growth and invasiveness in mice and severely impaired the formation of distant metastases. Likewise, in competitive tumor engraftment assays where we injected a 50:50 mixture of control and shPODXL (short-hairpin RNA targeting PODXL)-expressing cells, we found that podocalyxin-deficient cells exhibited a striking decrease in the ability to form clonal tumors in the lung, liver and bone marrow. Finally, to validate podocalyxin as a viable target for immunotherapy, we screened a series of novel antihuman podocalyxin antibodies for their ability to inhibit tumor progression in vivo. One of these antibodies, PODOC1, potently blocked tumor growth and metastasis. CONCLUSIONS: We show that podocalyxin plays a key role in the formation of primary tumors and distant tumor metastasis. In addition, we validate podocalyxin as potential target for monoclonal antibody therapy to inhibit primary tumor growth and systemic dissemination.
dc.description.statementofresponsibilityKimberly A Snyder, Michael R Hughes, Bradley Hedberg, Jill Brandon, Diana Canals Hernaez, Peter Bergqvist, Frederic Cruz, Kelvin Po, Marcia L Graves, Michelle E Turvey, Julie S Nielsen, John A Wilkins, Shaun R McColl, John S Babcook, Calvin D Roskelley, and Kelly M McNagny
dc.identifier.citationBreast Cancer Research, 2015; 17(1):46-1-46-46
dc.identifier.doi10.1186/s13058-015-0562-7
dc.identifier.issn1465-5411
dc.identifier.issn1465-542X
dc.identifier.orcidMcColl, S. [0000-0003-0949-4660]
dc.identifier.urihttp://hdl.handle.net/2440/92506
dc.language.isoen
dc.publisherBioMed Central
dc.relation.grantNHMRC
dc.rights© 2015 Snyder et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.source.urihttps://doi.org/10.1186/s13058-015-0562-7
dc.subjectCell Line, Tumor
dc.subjectSpheroids, Cellular
dc.subjectTumor Cells, Cultured
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBreast Neoplasms
dc.subjectMammary Neoplasms, Animal
dc.subjectCell Transformation, Neoplastic
dc.subjectNeoplasm Metastasis
dc.subjectDisease Models, Animal
dc.subjectSialoglycoproteins
dc.subjectRNA, Small Interfering
dc.subjectAntineoplastic Agents
dc.subjectAntibodies, Monoclonal
dc.subjectTumor Burden
dc.subjectXenograft Model Antitumor Assays
dc.subjectRNA Interference
dc.subjectFemale
dc.titlePodocalyxin enhances breast tumor growth and metastasis and is a target for monoclonal antibody therapy
dc.typeJournal article
pubs.publication-statusPublished

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