“Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”
Abstract 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 We generated 29 PDO lin...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13046-022-02591-z |
| _version_ | 1828069360723296256 |
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| author | Federica Papaccio Blanca García-Mico Francisco Gimeno-Valiente Manuel Cabeza-Segura Valentina Gambardella María Fernanda Gutiérrez-Bravo Clara Alfaro-Cervelló Carolina Martinez-Ciarpaglini Pilar Rentero-Garrido Sheila Zúñiga-Trejos Juan Antonio Carbonell-Asins Tania Fleitas Susana Roselló Marisol Huerta Manuel M. Sánchez del Pino Luís Sabater Desamparados Roda Noelia Tarazona Andrés Cervantes Josefa Castillo |
| author_facet | Federica Papaccio Blanca García-Mico Francisco Gimeno-Valiente Manuel Cabeza-Segura Valentina Gambardella María Fernanda Gutiérrez-Bravo Clara Alfaro-Cervelló Carolina Martinez-Ciarpaglini Pilar Rentero-Garrido Sheila Zúñiga-Trejos Juan Antonio Carbonell-Asins Tania Fleitas Susana Roselló Marisol Huerta Manuel M. Sánchez del Pino Luís Sabater Desamparados Roda Noelia Tarazona Andrés Cervantes Josefa Castillo |
| author_sort | Federica Papaccio |
| collection | DOAJ |
| description | Abstract 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 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 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 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. |
| first_indexed | 2024-04-11T00:19:58Z |
| format | Article |
| id | doaj.art-a72cfc5ee59741f4839fb4407bd9b3b0 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-04-11T00:19:58Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-a72cfc5ee59741f4839fb4407bd9b3b02023-01-08T12:23:37ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-01-0142112210.1186/s13046-022-02591-z“Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction”Federica Papaccio0Blanca García-Mico1Francisco Gimeno-Valiente2Manuel Cabeza-Segura3Valentina Gambardella4María Fernanda Gutiérrez-Bravo5Clara Alfaro-Cervelló6Carolina Martinez-Ciarpaglini7Pilar Rentero-Garrido8Sheila Zúñiga-Trejos9Juan Antonio Carbonell-Asins10Tania Fleitas11Susana Roselló12Marisol Huerta13Manuel M. Sánchez del Pino14Luís Sabater15Desamparados Roda16Noelia Tarazona17Andrés Cervantes18Josefa Castillo19Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of SalernoDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaUniversity College London Cancer Institute, Cancer Evolution and Genome Instability LaboratoryDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Pathology, Hospital Clínico Universitario, INCLIVA Biomedical Research Institute, University of ValenciaCentro de Investigación Biomédica en Red (CIBERONC), Instituto de Salud Carlos IIIPrecision Medicine Unit, INCLIVA Biomedical Research Institute, University of ValenciaBioinformatic and Biostatistic Unit, INCLIVA Biomedical Research Institute, University of ValenciaBioinformatic and Biostatistic Unit, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaUniversity Institute of Biotechnology and Biomedicine (BIOTECMED), University of ValenciaLiver, Biliary and Pancreatic Unit, Department of Surgery, Hospital Clínico Universitario of Valencia, University of Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaDepartment of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of ValenciaAbstract 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 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 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 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.https://doi.org/10.1186/s13046-022-02591-zColorectal cancerOrganoidsQuantitative proteomicsPrecision medicineDrug resistanceTranscriptomics |
| spellingShingle | Federica Papaccio Blanca García-Mico Francisco Gimeno-Valiente Manuel Cabeza-Segura Valentina Gambardella María Fernanda Gutiérrez-Bravo Clara Alfaro-Cervelló Carolina Martinez-Ciarpaglini Pilar Rentero-Garrido Sheila Zúñiga-Trejos Juan Antonio Carbonell-Asins Tania Fleitas Susana Roselló Marisol Huerta Manuel M. Sánchez del Pino Luís Sabater Desamparados Roda Noelia Tarazona Andrés Cervantes Josefa Castillo “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” Journal of Experimental & Clinical Cancer Research Colorectal cancer Organoids Quantitative proteomics Precision medicine Drug resistance Transcriptomics |
| title | “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” |
| title_full | “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” |
| title_fullStr | “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” |
| title_full_unstemmed | “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” |
| title_short | “Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction” |
| title_sort | proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity prediction |
| topic | Colorectal cancer Organoids Quantitative proteomics Precision medicine Drug resistance Transcriptomics |
| url | https://doi.org/10.1186/s13046-022-02591-z |
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