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

Maria Laura De Angelis, Federica Francescangeli, Chiara Nicolazzo, Michele Signore, Alessandro Giuliani, Lidia Colace, Alessandra Boe, Valentina Magri, Marta Baiocchi, Antonio Ciardi, Francesco Scarola, Massimo Spada, Filippo La Torre, Paola Gazzaniga, Mauro Biffoni, Ruggero De Maria Marchiano, Ann Zeuner

Risultato della ricerca: Contributo in rivistaArticolo in rivista

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.
Lingua originaleEnglish
pagine (da-a)86-N/A
RivistaJOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
Volume41
DOI
Stato di pubblicazionePubblicato - 2022

Keywords

  • Biomarkers, Tumor
  • Cancer stem cells
  • Circulating tumor cells
  • Colorectal Neoplasms
  • Colorectal cancer
  • Epithelial-Mesenchymal Transition
  • Humans
  • Metastasis
  • Neoplastic Cells, Circulating
  • Organoids
  • Stem Cells

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