"Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction".

Humans Antineoplastic Agents / pharmacology Oxaliplatin / pharmacology Proteomics Colorectal Neoplasms / drug therapy Organoids
Colorectal cancer Drug resistance Organoids Precision medicine Proteotranscriptomics integrative functional network analysis Quantitative proteomics Transcriptomics

Journal

Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647

Informations de publication

Date de publication:
06 Jan 2023
Historique:
received: 28 09 2022
accepted: 28 12 2022
entrez: 5 1 2023
pubmed: 6 1 2023
medline: 10 1 2023
Statut: epublish

Résumé

Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics. We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively. PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs. Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.

Sections du résumé

BACKGROUND BACKGROUND
Patient-derived organoids (PDOs) from advanced colorectal cancer (CRC) patients could be a key platform to predict drug response and discover new biomarkers. We aimed to integrate PDO drug response with multi-omics characterization beyond genomics.
METHODS METHODS
We generated 29 PDO lines from 22 advanced CRC patients and provided a morphologic, genomic, and transcriptomic characterization. We performed drug sensitivity assays with a panel of both standard and non-standard agents in five long-term cultures, and integrated drug response with a baseline proteomic and transcriptomic characterization by SWATH-MS and RNA-seq analysis, respectively.
RESULTS RESULTS
PDOs were successfully generated from heavily pre-treated patients, including a paired model of advanced MSI high CRC deriving from pre- and post-chemotherapy liver metastasis. Our PDOs faithfully reproduced genomic and phenotypic features of original tissue. Drug panel testing identified differential response among PDOs, particularly to oxaliplatin and palbociclib. Proteotranscriptomic analyses revealed that oxaliplatin non-responder PDOs present enrichment of the t-RNA aminoacylation process and showed a shift towards oxidative phosphorylation pathway dependence, while an exceptional response to palbociclib was detected in a PDO with activation of MYC and enrichment of chaperonin T-complex protein Ring Complex (TRiC), involved in proteome integrity. Proteotranscriptomic data fusion confirmed these results within a highly integrated network of functional processes involved in differential response to drugs.
CONCLUSIONS CONCLUSIONS
Our strategy of integrating PDOs drug sensitivity with SWATH-mass spectrometry and RNA-seq allowed us to identify different baseline proteins and gene expression profiles with the potential to predict treatment response/resistance and to help in the development of effective and personalized cancer therapeutics.

Identifiants

DOI: 10.1186/s13046-022-02591-z PMID: 36604765 PMC: PMC9817273
pubmed: 36604765
doi: 10.1186/s13046-022-02591-z
pii: 10.1186/s13046-022-02591-z
pmc: PMC9817273
doi:

Substances chimiques

Antineoplastic Agents 0
Oxaliplatin 04ZR38536J

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

8

Subventions

Organisme : Instituto de Salud Carlos III
ID : PI18/01508
Organisme : Instituto de Salud Carlos III
ID : PI21/0693
Organisme : Instituto de Salud Carlos III
ID : PI18/01909
Organisme : Instituto de Salud Carlos III
ID : PI18/01909
Organisme : Instituto de Salud Carlos III
ID : PI21/00689
Organisme : Instituto de Salud Carlos III
ID : PI21/00689
Organisme : Instituto de Salud Carlos III
ID : Joan Rodés contract JR17/00026
Organisme : Instituto de Salud Carlos III
ID : Joan Rodés contract JR21/00042
Organisme : Instituto de Salud Carlos III
ID : Joan Rodés contract JR20/00005
Organisme : Instituto de Salud Carlos III
ID : Joan Rodés contract JR16/00040
Organisme : Instituto de Salud Carlos III
ID : 2018 grant
Organisme : Fundación Científica Asociación Española Contra el Cáncer
ID : predoctoral grant
Organisme : Generalitat Valenciana
ID : APOSTD/2021/168
Organisme : Generalitat Valenciana
ID : PROMETEU/2019/065
Organisme : Universitat de València and INCLIVA
ID : VLC Bioclinic grant 2021/257
Organisme : Universitat de València and INCLIVA
ID : VLC Bioclinic grant 2021/257
Organisme : European Society for Medical Oncology
ID : ESMO Translational Research Fellowship 2018-2020
Organisme : Conselleria d'Educació, Investigació, Cultura i Esport
ID : GRISOLIAP/2017/161
Organisme : Ministerio de Ciencia e Innovación
ID : PID2020-119111GB-I00

Informations de copyright

© 2023. The Author(s).

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Auteurs

Federica Papaccio (F)

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, Italy. fpapaccio@unisa.it.
Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain. fpapaccio@unisa.it.

Blanca García-Mico (B)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Francisco Gimeno-Valiente (F)

University College London Cancer Institute, Cancer Evolution and Genome Instability Laboratory, London, UK.

Manuel Cabeza-Segura (M)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Valentina Gambardella (V)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.

María Fernanda Gutiérrez-Bravo (MF)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Health Sciences Faculty, Universidad Internacional SEK (UISEK), Quito, 170120, Ecuador.

Clara Alfaro-Cervelló (C)

Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Carolina Martinez-Ciarpaglini (C)

Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.
Department of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Pilar Rentero-Garrido (P)

Precision Medicine Unit, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Sheila Zúñiga-Trejos (S)

Bioinformatic and Biostatistic Unit, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Juan Antonio Carbonell-Asins (JA)

Bioinformatic and Biostatistic Unit, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Tania Fleitas (T)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.

Susana Roselló (S)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.

Marisol Huerta (M)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Manuel M Sánchez Del Pino (MM)

University Institute of Biotechnology and Biomedicine (BIOTECMED), University of Valencia, 46100, Burjassot, Spain.
Department of Biochemistry and Molecular Biology, Universitat de València, 46100, Burjassot, Spain.

Luís Sabater (L)

Liver, Biliary and Pancreatic Unit, Department of Surgery, Hospital Clínico Universitario of Valencia, University of Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.

Desamparados Roda (D)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.

Noelia Tarazona (N)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain.

Andrés Cervantes (A)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain. andres.cervantes@uv.es.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain. andres.cervantes@uv.es.
ORCID: 0000-0003-3806-3691

Josefa Castillo (J)

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010, Valencia, Spain. pepa.castillo@uv.es.
Centro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos III, 28029, Madrid, Spain. pepa.castillo@uv.es.
Department of Biochemistry and Molecular Biology, Universitat de València, 46100, Burjassot, Spain. pepa.castillo@uv.es.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › "Proteotranscriptomic analysis of advanced...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › "Proteotranscriptomic analysis of advanced...
questionsmedicales.fr › Composés chimiques organiques › Complexes de coordination › Oxaliplatine › "Proteotranscriptomic analysis of advanced...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › "Proteotranscriptomic analysis of advanced...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › "Proteotranscriptomic analysis of advanced...
questionsmedicales.fr › Tissus › Organoïdes › "Proteotranscriptomic analysis of advanced...