Integrated multi-omics analyses on patient-derived CRC organoids highlight altered molecular pathways in colorectal cancer progression involving PTEN.

Autor: Codrich M; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy., Dalla E; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy., Mio C; Institute of Medical Genetics, Department of Medicine, University of Udine, 33100, Udine, Italy., Antoniali G; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy., Malfatti MC; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy., Marzinotto S; Piattaforma Specializzata Centro Servizi e Laboratori, Area Biologia Molecolare, Colture Cellulari e Supporto, Azienda Sanitaria Universitaria Friuli Centrale, 33100, Udine, Italy., Pierobon M; School of Systems Biology, Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20108, USA., Baldelli E; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, 20108, USA., Di Loreto C; Pathology Unit, Department of Medicine, University of Udine, 33100, Udine, Italy., Damante G; Institute of Medical Genetics, Department of Medicine, University of Udine, 33100, Udine, Italy., Terrosu G; General Surgery and Transplantation Unit, Department of Medicine, University of Udine, 33100, Udine, Italy., Pucillo CEM; Laboratory of Immunology, Department of Medicine, University of Udine, 33100, Udine, Italy., Tell G; Laboratory of Molecular Biology and DNA Repair, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, 33100, Udine, Italy. gianluca.tell@uniud.it.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2021 Jun 21; Vol. 40 (1), pp. 198. Date of Electronic Publication: 2021 Jun 21.
DOI: 10.1186/s13046-021-01986-8
Abstrakt: Background: Colorectal cancer (CRC) represents the fourth leading cause of cancer-related deaths. The heterogeneity of CRC identity limits the usage of cell lines to study this type of tumor because of the limited representation of multiple features of the original malignancy. Patient-derived colon organoids (PDCOs) are a promising 3D-cell model to study tumor identity for personalized medicine, although this approach still lacks detailed characterization regarding molecular stability during culturing conditions. Correlation analysis that considers genomic, transcriptomic, and proteomic data, as well as thawing, timing, and culturing conditions, is missing.
Methods: Through integrated multi-omics strategies, we characterized PDCOs under different growing and timing conditions, to define their ability to recapitulate the original tumor.
Results: Whole Exome Sequencing allowed detecting temporal acquisition of somatic variants, in a patient-specific manner, having deleterious effects on driver genes CRC-associated. Moreover, the targeted NGS approach confirmed that organoids faithfully recapitulated patients' tumor tissue. Using RNA-seq experiments, we identified 5125 differentially expressed transcripts in tumor versus normal organoids at different time points, in which the PTEN pathway resulted of particular interest, as also confirmed by further phospho-proteomics analysis. Interestingly, we identified the PTEN c.806_817dup (NM_000314) mutation, which has never been reported previously and is predicted to be deleterious according to the American College of Medical Genetics and Genomics (ACMG) classification.
Conclusion: The crosstalk of genomic, transcriptomic and phosphoproteomic data allowed to observe that PDCOs recapitulate, at the molecular level, the tumor of origin, accumulating mutations over time that potentially mimic the evolution of the patient's tumor, underlining relevant potentialities of this 3D model.
Databáze: MEDLINE
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