An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile

Journal of Experimental & Clinical Cancer Research

Massimo Spada¹  Alessandra Boe²  Chiara Nicolazzo³  Paola Gazzaniga³  Marta Baiocchi⁴  Federica Francescangeli⁴  Mauro Biffoni⁴  Maria Laura De Angelis⁴  Ann Zeuner⁴  Valentina Magri⁵  Francesco Scarola⁶  Antonio Ciardi⁶  Lidia Colace⁷  Ruggero De Maria⁸  Alessandro Giuliani⁹  Michele Signore^1,10  Filippo La Torre^1,11 

[1] Center of Animal Research and Welfare, Istituto Superiore di Sanità;Core Facilities, Istituto Superiore di Sanità;Department of Molecular Medicine, Liquid Biopsy Unit, Sapienza University;Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità;Department of Radiological, Oncological and Pathological Sciences, Sapienza University;Department of Surgery “Pietro Valdoni”, Policlinico Umberto I/Sapienza University;Department of Surgical Sciences, Policlinico Umberto I/Sapienza University of Rome;Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore;Environment and Health Department, Istituto Superiore di Sanità;RPPA Unit, Proteomics Area, Core Facilities, Istituto Superiore di Sanità;Surgical Sciences and Emergency Department, Policlinico Umberto I/Sapienza University of Rome;

关键词: Circulating tumor cells;    Colorectal cancer;    Organoids;    Metastasis;    Cancer stem cells;   

DOI  :  10.1186/s13046-022-02263-y

来源: DOAJ

【 摘 要 】

Abstract Background Circulating tumor cells (CTCs) are responsible for the metastatic dissemination of colorectal cancer (CRC) to the liver, lungs and lymph nodes. CTCs rarity and heterogeneity strongly limit the elucidation of their biological features, as well as preclinical drug sensitivity studies aimed at metastasis prevention. Methods We generated organoids from CTCs isolated from an orthotopic CRC xenograft model. CTCs-derived organoids (CTCDOs) were characterized through proteome profiling, immunohistochemistry, immunofluorescence, flow cytometry, tumor-forming capacity and drug screening assays. The expression of intra- and extracellular markers found in CTCDOs was validated on CTCs isolated from the peripheral blood of CRC patients. Results CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. Functionally, CTCDOs showed a higher migratory/invasive ability and a different response to pathway-targeted drugs as compared to xenograft-derived organoids (XDOs). Specifically, CTCDOs were more sensitive than XDOs to drugs affecting the Survivin pathway, which decreased the levels of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) inducing CTCDOs death. Conclusions These results indicate that CTCDOs recapitulate several features of colorectal CTCs and may be used to investigate the features of metastatic CRC cells, to identify new prognostic biomarkers and to devise new potential strategies for metastasis prevention.

【 授权许可】

Unknown