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Decellularized extracellular matrix as scaffold for cancer organoid cultures of colorectal peritoneal metastases

Journal of Molecular Cell Biology 2022年第11期14卷 36-49页

作者： Luca Varinelli Marcello Guaglio Silvia Brich Susanna Zanutto Antonino Belfiore Federica Zanardi Fabio Iannelli Amanda Oldani Elisa Costa Matteo Chighizola Ewelina Lorenc Simone P.Minardi Stefano Fortuzzi Martina Filugelli Giovanna Garzone Federica Pisati Manuela Vecchi giancarlo pruneri Shigeki Kusamura Dario Baratti Laura Cattaneo Dario Parazzoli Alessandro Podestà Massimo Milione Marcello Deraco Marco A.Pierotti Manuela Gariboldi Department of Research Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Peritoneal Surface Malignancies Unit Colon and Rectal SurgeryFondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Department of Pathology and Laboratory Medicine Clinical Research lABoratory(CRAB)Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly Bioinformatics Core Unit IFOM ETSThe AIRC Institute of Molecular Oncologyvia Adamello 1620139 MilanItaly Imaging Technological Development Unit IFOM ETSThe AIRC Institute of Molecular Oncologyvia Adamello 1620139 MilanItaly C.I.Ma.I.Na.and Dipartimento di Fisica‘Aldo Pontremoli’ Universitàdegli Studi di Milanovia G.Celoria 1620133 MilanItaly Cogentech Ltd Benefit Corporation with a Sole Shareholder via Adamello 1620139 MilanItaly Pathology and Laboratory Medicine Department Fondazione IRCCS Istituto Nazionale dei Tumorivia G.Venezian 120133 MilanItaly

Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ECM) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions between metastatic cells and the ECM, however, remain poorly understood, and the number of in vitro models available for the study of the peritoneal metastatic process is limited. Here, we show that decellularized ECM of the peritoneal cavity allows the growth of organoids obtained from PM, favoring the development of three-dimensional (3D) nodules that maintain the characteristics of in vivo PM. Organoids preferentially grow on scaffolds obtained from neoplastic peritoneum, which are characterized by greater stiffness than normal scaffolds. A gene expression analysis of organoids grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. An impact of the ECM on the response to standard chemotherapy treatment for PM was also observed. The ex vivo 3D model, obtained by combining patient-derived decellularized ECM with organoids to mimic the metastatic niche, could be an innovative tool to develop new therapeutic strategies in a biologically relevant context to personalize treatments.

关键词： colorectal cancer peritoneal metastasis organoids extracellular matrix(ECM) decellularized extracellular matrix engineered disease model ECM stiffness

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