TY - JOUR
T1 - An organoid model of colorectal circulating tumor cells with stem cell features, hybrid EMT state and distinctive therapy response profile
AU - De Angelis, Maria Laura
AU - Francescangeli, Federica
AU - Nicolazzo, Chiara
AU - Signore, Michele
AU - Giuliani, Alessandro
AU - Colace, Lidia
AU - Boe, Alessandra
AU - Magri, Valentina
AU - Baiocchi, Marta
AU - Ciardi, Antonio
AU - Scarola, Francesco
AU - Spada, Massimo
AU - La Torre, Filippo
AU - Gazzaniga, Paola
AU - Biffoni, Mauro
AU - De Maria Marchiano, Ruggero
AU - Zeuner, Ann
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Biomarkers, Tumor
KW - Cancer stem cells
KW - Circulating tumor cells
KW - Colorectal Neoplasms
KW - Colorectal cancer
KW - Epithelial-Mesenchymal Transition
KW - Humans
KW - Metastasis
KW - Neoplastic Cells, Circulating
KW - Organoids
KW - Stem Cells
KW - Biomarkers, Tumor
KW - Cancer stem cells
KW - Circulating tumor cells
KW - Colorectal Neoplasms
KW - Colorectal cancer
KW - Epithelial-Mesenchymal Transition
KW - Humans
KW - Metastasis
KW - Neoplastic Cells, Circulating
KW - Organoids
KW - Stem Cells
UR - http://hdl.handle.net/10807/206008
U2 - 10.1186/s13046-022-02263-y
DO - 10.1186/s13046-022-02263-y
M3 - Article
SN - 0392-9078
VL - 41
SP - 86-N/A
JO - JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
JF - JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
ER -