An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer

[Background]: Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc. [Methods]: Western blot and immunohistochemi...

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Detalles Bibliográficos
Autores: Montero, Juan Carlos, Carmen, Sofía del, Abad, Mar, Sayagués, José María, Barbáchano, Antonio, Fernández-Barral, Asunción, Muñoz Terol, Alberto, Pandiella, Atanasio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/346897
Acceso en línea:http://hdl.handle.net/10261/346897
Access Level:acceso abierto
Palabra clave:CD98hc
Antibody–drug conjugates
Colorectal cancer
Targeted therapy
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dc.title.none.fl_str_mv An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
title An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
spellingShingle An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
Montero, Juan Carlos
CD98hc
Antibody–drug conjugates
Colorectal cancer
Targeted therapy
title_short An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
title_full An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
title_fullStr An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
title_full_unstemmed An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
title_sort An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer
dc.creator.none.fl_str_mv Montero, Juan Carlos
Carmen, Sofía del
Abad, Mar
Sayagués, José María
Barbáchano, Antonio
Fernández-Barral, Asunción
Muñoz Terol, Alberto
Pandiella, Atanasio
author Montero, Juan Carlos
author_facet Montero, Juan Carlos
Carmen, Sofía del
Abad, Mar
Sayagués, José María
Barbáchano, Antonio
Fernández-Barral, Asunción
Muñoz Terol, Alberto
Pandiella, Atanasio
author_role author
author2 Carmen, Sofía del
Abad, Mar
Sayagués, José María
Barbáchano, Antonio
Fernández-Barral, Asunción
Muñoz Terol, Alberto
Pandiella, Atanasio
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Junta de Castilla y León
Fundación CRIS contra el Cáncer
Agencia Estatal de Investigación (España)
European Commission
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv CD98hc
Antibody–drug conjugates
Colorectal cancer
Targeted therapy
topic CD98hc
Antibody–drug conjugates
Colorectal cancer
Targeted therapy
description [Background]: Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc. [Methods]: Western blot and immunohistochemical analyses of CD98hc protein expression were carried out on paired normal and tumoral tissues from patients with CRC. Immunofluorescence and western studies were used to characterize the action of a DM1-based CD98hc-directed antibody–drug conjugate (ADC). MTT and Annexin V studies were performed to evaluate the effect of the anti-CD98hc-ADC on cell proliferation and apoptosis. CRISPR/Cas9 and shRNA were used to explore the specificity of the ADC. In vitro analyses of the antitumoral activity of the anti-CD98hc-ADC on 3D patient-derived normal as well as tumoral organoids were also carried out. Xenografted CRC cells and a PDX were used to analyze the antitumoral properties of the anti-CD98hc-ADC. [Results]: Genomic as well proteomic analyses of paired normal and tumoral samples showed that CD98hc expression was significantly higher in tumoral tissues as compared to levels of CD98hc present in the normal colonic tissue. In human CRC cell lines, an ADC that recognized the CD98hc ectodomain, reached the lysosomes and exerted potent antitumoral activity. The specificity of the CD98hc-directed ADC was demonstrated using CRC cells in which CD98hc was decreased by shRNA or deleted using CRISPR/Cas9. Studies in patient-derived organoids verified the antitumoral action of the anti-CD98hc-ADC, which largely spared normal tissue-derived colon organoids. In vivo studies using xenografted CRC cells or patient-derived xenografts confirmed the antitumoral activity of the anti-CD98hc-ADC. [Conclusions]: The studies herewith reported indicate that CD98hc may represent a novel ADC target that, upon well-designed clinical trials, could be used to increase the therapeutic armamentarium against CRC.
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2024
2024
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Publisher's version
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/346897
url http://hdl.handle.net/10261/346897
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115605RB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104867RB-I00
Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 1 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916982.v1
Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 2 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916985.v1
Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 3 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916988.v1
Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 4 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916991.v1
http://dx.doi.org/10.1186/s13046-023-02784-0
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dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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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
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spelling An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancerMontero, Juan CarlosCarmen, Sofía delAbad, MarSayagués, José MaríaBarbáchano, AntonioFernández-Barral, AsunciónMuñoz Terol, AlbertoPandiella, AtanasioCD98hcAntibody–drug conjugatesColorectal cancerTargeted therapy[Background]: Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc. [Methods]: Western blot and immunohistochemical analyses of CD98hc protein expression were carried out on paired normal and tumoral tissues from patients with CRC. Immunofluorescence and western studies were used to characterize the action of a DM1-based CD98hc-directed antibody–drug conjugate (ADC). MTT and Annexin V studies were performed to evaluate the effect of the anti-CD98hc-ADC on cell proliferation and apoptosis. CRISPR/Cas9 and shRNA were used to explore the specificity of the ADC. In vitro analyses of the antitumoral activity of the anti-CD98hc-ADC on 3D patient-derived normal as well as tumoral organoids were also carried out. Xenografted CRC cells and a PDX were used to analyze the antitumoral properties of the anti-CD98hc-ADC. [Results]: Genomic as well proteomic analyses of paired normal and tumoral samples showed that CD98hc expression was significantly higher in tumoral tissues as compared to levels of CD98hc present in the normal colonic tissue. In human CRC cell lines, an ADC that recognized the CD98hc ectodomain, reached the lysosomes and exerted potent antitumoral activity. The specificity of the CD98hc-directed ADC was demonstrated using CRC cells in which CD98hc was decreased by shRNA or deleted using CRISPR/Cas9. Studies in patient-derived organoids verified the antitumoral action of the anti-CD98hc-ADC, which largely spared normal tissue-derived colon organoids. In vivo studies using xenografted CRC cells or patient-derived xenografts confirmed the antitumoral activity of the anti-CD98hc-ADC. [Conclusions]: The studies herewith reported indicate that CD98hc may represent a novel ADC target that, upon well-designed clinical trials, could be used to increase the therapeutic armamentarium against CRC.JCM: Instituto de Salud Carlos III through a Miguel Servet program (CPII17/00015) and (PI18/00796). AP: Ministry of Economy and Competitiveness of Spain (PID2020-115605RB-I00), the Instituto de Salud Carlos III through CIBERONC, Junta de Castilla y León (CSI146P20), ALMOM, ACMUMA, UCCTA, and the CRIS Cancer Foundation. AM, AB and AF-B: Instituto de Salud Carlos III (ICI20/00057, CIBERONC/CB16/12/00273) and Agencia Estatal de Investigación (PID2019-104867RB-I00/AEI/10.13039/501100011033). The work described here was co-funded by the European Community through the European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future".Peer reviewedBioMed CentralInstituto de Salud Carlos IIIMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Junta de Castilla y LeónFundación CRIS contra el CáncerAgencia Estatal de Investigación (España)European CommissionConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420232024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/346897reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-115605RB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-104867RB-I00Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 1 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916982.v1Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 2 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916985.v1Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 3 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916988.v1Montero, Juan Carlos; Carmen, Sofía del; Abad, Mar; Sayagués, José María; Barbáchano, Antonio; Fernández-Barral, Asunción; Muñoz, Alberto; Pandiella, Atanasio; 2023; Additional file 4 of An amino acid transporter subunit as an antibody–drug conjugate target in colorectal cancer [Dataset]; Figshare; https://doi.org/10.6084/m9.figshare.23916991.v1http://dx.doi.org/10.1186/s13046-023-02784-0Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3468972026-05-22T06:33:51Z
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