Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer

[Background]: Despite the incorporation of novel therapeutics, advanced triple negative breast cancer (TNBC) still represents a relevant clinical problem. Considering this, as well as the clinical efficacy of antibody-drug conjugates (ADCs), we aimed at identifying novel ADC targets that could be us...

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Autores: Montero, Juan Carlos, Calvo-Jiménez, Elisa, Carmen, Sofía del, Abad, María del Mar, Ocaña, Alberto, Pandiella, Atanasio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/283384
Acceso en línea:http://hdl.handle.net/10261/283384
Access Level:acceso abierto
Palabra clave:CD98hc
Antibody-drug conjugates
Triple negative breast cancer
Targeted therapy
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
title Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
spellingShingle Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
Montero, Juan Carlos
CD98hc
Antibody-drug conjugates
Triple negative breast cancer
Targeted therapy
title_short Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
title_full Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
title_fullStr Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
title_full_unstemmed Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
title_sort Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer
dc.creator.none.fl_str_mv Montero, Juan Carlos
Calvo-Jiménez, Elisa
Carmen, Sofía del
Abad, María del Mar
Ocaña, Alberto
Pandiella, Atanasio
author Montero, Juan Carlos
author_facet Montero, Juan Carlos
Calvo-Jiménez, Elisa
Carmen, Sofía del
Abad, María del Mar
Ocaña, Alberto
Pandiella, Atanasio
author_role author
author2 Calvo-Jiménez, Elisa
Carmen, Sofía del
Abad, María del Mar
Ocaña, Alberto
Pandiella, Atanasio
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Ministerio de Economía y Competitividad (España)
Junta de Castilla y León
Fundación CRIS contra el Cáncer
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CD98hc
Antibody-drug conjugates
Triple negative breast cancer
Targeted therapy
topic CD98hc
Antibody-drug conjugates
Triple negative breast cancer
Targeted therapy
description [Background]: Despite the incorporation of novel therapeutics, advanced triple negative breast cancer (TNBC) still represents a relevant clinical problem. Considering this, as well as the clinical efficacy of antibody-drug conjugates (ADCs), we aimed at identifying novel ADC targets that could be used to treat TNBC. [Methods]: Transcriptomic analyses were performed on TNBC and normal samples from three different studies. Plasma membrane proteins of three cell lines representative of the TNBC subtype were identified by cell surface biotinylation or plasma membrane isolation, followed by analyses of cell surface proteins using the Surfaceome online tool. Immunofluorescence and western studies were used to characterize the action of a CD98hc-directed ADC, which was prepared by in house coupling of emtansine to an antibody that recognized the ectodomain of CD98hc. Xenografted TNBC cells were used to analyze the antitumoral properties of the anti-CD98hc ADC. [Results]: Comparative genomic studies between normal breast and TNBC tissues, together with proteomic and bioinformatic analyses resulted in the elaboration of a catalog of potential ADC targets. One of them, the CD98hc transmembrane protein, was validated as an ADC target. An antibody recognizing the ectodomain of CD98hc efficiently internalized and reached the lysosomal compartment. An emtansine-based ADC derived from such antibody was prepared and showed antitumoral properties in TNBC in vitro and in vivo models. Mechanistically, the anti-CD98hc ADC blocked cell cycle progression, that was followed by cell death caused by mitotic catastrophe. [Conclusions]: This work describes a list of potential ADC targets in TNBC and validates one of them, the transmembrane protein CD98hc. The studies presented here also demonstrate the robustness of the multiomic approach herewith described to identify novel potential ADC targets.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/283384
url http://hdl.handle.net/10261/283384
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//BFU2015-71371-R
Montero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 1 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401960.v1
Montero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 2 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401963.v1
Montero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 3 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401966.v1
http://dx.doi.org/10.1186/s13046-022-02330-4
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancerMontero, Juan CarlosCalvo-Jiménez, ElisaCarmen, Sofía delAbad, María del MarOcaña, AlbertoPandiella, AtanasioCD98hcAntibody-drug conjugatesTriple negative breast cancerTargeted therapy[Background]: Despite the incorporation of novel therapeutics, advanced triple negative breast cancer (TNBC) still represents a relevant clinical problem. Considering this, as well as the clinical efficacy of antibody-drug conjugates (ADCs), we aimed at identifying novel ADC targets that could be used to treat TNBC. [Methods]: Transcriptomic analyses were performed on TNBC and normal samples from three different studies. Plasma membrane proteins of three cell lines representative of the TNBC subtype were identified by cell surface biotinylation or plasma membrane isolation, followed by analyses of cell surface proteins using the Surfaceome online tool. Immunofluorescence and western studies were used to characterize the action of a CD98hc-directed ADC, which was prepared by in house coupling of emtansine to an antibody that recognized the ectodomain of CD98hc. Xenografted TNBC cells were used to analyze the antitumoral properties of the anti-CD98hc ADC. [Results]: Comparative genomic studies between normal breast and TNBC tissues, together with proteomic and bioinformatic analyses resulted in the elaboration of a catalog of potential ADC targets. One of them, the CD98hc transmembrane protein, was validated as an ADC target. An antibody recognizing the ectodomain of CD98hc efficiently internalized and reached the lysosomal compartment. An emtansine-based ADC derived from such antibody was prepared and showed antitumoral properties in TNBC in vitro and in vivo models. Mechanistically, the anti-CD98hc ADC blocked cell cycle progression, that was followed by cell death caused by mitotic catastrophe. [Conclusions]: This work describes a list of potential ADC targets in TNBC and validates one of them, the transmembrane protein CD98hc. The studies presented here also demonstrate the robustness of the multiomic approach herewith described to identify novel potential ADC targets.JCM is funded by the Instituto de Salud Carlos III through a Miguel Servet program (CP12/03073 and CPII17/00015) and receives research support from the same institution (PI15/00684 and PI18/00796) (Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). AP: Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R); Instituto de Salud Carlos III through CIBERONC; Junta de Castilla y León (CSI146P20); CRIS Cancer Foundation, ACMUMA, UCCTA, and ALMOM. Work carried out in our laboratories receives support from the European Community through the Regional Development Funding Program (FEDER).BioMed CentralInstituto de Salud Carlos IIIEuropean CommissionMinisterio de Economía y Competitividad (España)Junta de Castilla y LeónFundación CRIS contra el CáncerConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/283384reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//BFU2015-71371-RMontero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 1 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401960.v1Montero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 2 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401963.v1Montero, Juan Carlos; Calvo-Jiménez, Elisa; Carmen, Sofía del; Abad, María del Mar; Ocaña, Alberto; Pandiella, Atanasio; 2022; Additional file 3 of Surfaceome analyses uncover CD98hc as an antibody drug-conjugate target in triple negative breast cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.19401966.v1http://dx.doi.org/10.1186/s13046-022-02330-4Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2833842026-05-22T06:33:51Z
score 15.812429

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