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

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 fro...

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Bibliographic Details
Authors: Papaccio, Federica, Garcia-Mico, Blanca, Gimeno-Valiente, Francisco, Cabeza-Segura, Manuel, Gambardella, Valentina, Gutierrez-Bravo, Maria Fernanda, Alfaro-Cervello, Clara, Martinez-Ciarpaglini, Carolina, Rentero-Garrido, Pilar, Zuniga-Trejos, Sheila, Carbonell-Asins, Juan Antonio, Fleitas, Tania, Rosello, Susana, Huerta, Marisol, Sanchez Del Pino, Manuel M, Sabater, Luis, Roda, Desamparados, Tarazona, Noelia, Cervantes, Andres, Castillo, Josefa
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:INCLIVA
Repository:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p17124
Online Access:https://incliva.portalinvestigacion.com/publicaciones/17124
Access Level:Open access
Keyword:Colorectal cancer
Organoids
Quantitative proteomics
Precision medicine
Drug resistance
Transcriptomics
Proteotranscriptomics integrative functional network analysis
Description
Summary: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.

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