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.

An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile / De Angelis, Maria Laura; Francescangeli, Federica; Nicolazzo, Chiara; Signore, Michele; Giuliani, Alessandro; Colace, Lidia; Boe, Alessandra; Magri, Valentina; Baiocchi, Marta; Ciardi, Antonio; Scarola, Francesco; Spada, Massimo; La Torre, Filippo; Gazzaniga, Paola; Biffoni, Mauro; De Maria, Ruggero; Zeuner, Ann. - In: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH. - ISSN 1756-9966. - 41:1(2022). [10.1186/s13046-022-02263-y]

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

Nicolazzo, Chiara;Colace, Lidia;Magri, Valentina;Ciardi, Antonio;Scarola, Francesco;La Torre, Filippo;Gazzaniga, Paola;
2022

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.
2022
circulating tumor cells; colorectal cancer; organoids; metastasis; cancer stem cells
01 Pubblicazione su rivista::01a Articolo in rivista
An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile / De Angelis, Maria Laura; Francescangeli, Federica; Nicolazzo, Chiara; Signore, Michele; Giuliani, Alessandro; Colace, Lidia; Boe, Alessandra; Magri, Valentina; Baiocchi, Marta; Ciardi, Antonio; Scarola, Francesco; Spada, Massimo; La Torre, Filippo; Gazzaniga, Paola; Biffoni, Mauro; De Maria, Ruggero; Zeuner, Ann. - In: JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH. - ISSN 1756-9966. - 41:1(2022). [10.1186/s13046-022-02263-y]
File allegati a questo prodotto
File Dimensione Formato  
De Angelis_An organoid model_2022.pdf

accesso aperto

Note: https://jeccr.biomedcentral.com/articles/10.1186/s13046-022-02263-y
Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 3.29 MB
Formato Adobe PDF
3.29 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1616972
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 24
  • ???jsp.display-item.citation.isi??? 24
social impact