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

Authors :
Marta Codrich
Emiliano Dalla
Catia Mio
Giulia Antoniali
Matilde Clarissa Malfatti
Stefania Marzinotto
Mariaelena Pierobon
Elisa Baldelli
Carla Di Loreto
Giuseppe Damante
Giovanni Terrosu
Carlo Ennio Michele Pucillo
Gianluca Tell
Source :
Journal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-17 (2021)
Publication Year :
2021
Publisher :
BMC, 2021.

Abstract

Abstract 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.

Details

Language :
English
ISSN :
17569966
Volume :
40
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Journal of Experimental & Clinical Cancer Research
Publication Type :
Academic Journal
Accession number :
edsdoj.6e0b3cedf67c401c84c334288fd77d63
Document Type :
article
Full Text :
https://doi.org/10.1186/s13046-021-01986-8