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"Proteotranscriptomic analysis of advanced colorectal cancer patient derived organoids for drug sensitivity
Federica Papaccio1,2, Blanca García-Mico3, Francisco Gimeno-Valiente4
1Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, Italy. fpapaccio@unisa.it.
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.
Insights
Patient-derived organoids (PDOs) from colorectal cancer (CRC) patients predict drug response. Integrating multi-omics data with PDO drug sensitivity reveals biomarkers for personalized CRC therapeutics.
Area of Science:
- Oncology
- Translational Medicine
- Biomarker Discovery
Background:
- Patient-derived organoids (PDOs) are crucial for predicting drug response in advanced colorectal cancer (CRC).
- Integrating multi-omics data with PDOs offers a powerful approach beyond genomics for biomarker discovery.
- Current limitations exist in predicting treatment efficacy for advanced CRC patients.
Purpose of the Study:
- To integrate PDO drug response data with multi-omics (proteomic and transcriptomic) characterization.
- To identify baseline molecular profiles that predict drug sensitivity or resistance in advanced CRC.
- To establish a predictive platform for personalized CRC therapeutics.
Main Methods:
- Generated 29 PDO lines from 22 advanced CRC patients.
- Performed drug sensitivity assays with standard and non-standard agents.
- Integrated drug response data with proteomic (SWATH-MS) and transcriptomic (RNA-seq) analyses.
Main Results:
- PDOs successfully modeled advanced CRC, including pre- and post-chemotherapy samples.
- Differential drug responses were observed, notably to oxaliplatin and palbociclib.
- Proteotranscriptomic analyses identified distinct molecular pathways associated with drug response/resistance, such as t-RNA aminoacylation and oxidative phosphorylation for oxaliplatin, and MYC/TRiC for palbociclib.
Conclusions:
- Integrating PDO drug sensitivity with proteomic and transcriptomic data identifies predictive biomarkers for CRC treatment.
- This strategy facilitates the development of effective and personalized cancer therapeutics.
- Baseline molecular profiles can predict treatment response and resistance in advanced CRC.
