A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells

Isabel Puig, Irene Chicote, Stephan P. Tenbaum, Oriol Arqués, José Raúl Herance, Juan D. Gispert, José Jimenez, Stefania Landolfi, Karina Caci, Helena Allende, Leire Mendizabal, Debora Moreno, Ramón Charco, Eloy Espín, Aleix Prat, Maria Elena Elez, Guillem Argilés, Ana Vivancos, Josep Tabernero, Santiago RojasHéctor G. Palmer

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Abstract

Purpose: Within the aim of advancing precision oncology, we have generated a collection of patientderived xenografts (PDX) characterized at the molecular level, and a preclinical model of colon cancer metastasis to evaluate drug-response and tumor progression. Experimental Design: We derived cells from 32 primary colorectal carcinomas and eight liver metastases and generated PDX annotated for their clinical data, gene expression, mutational, and histopathological traits. Six models were injected orthotopically into the cecum wall of NOD-SCID mice in order to evaluate metastasis. Three of them were treated with chemotherapy (oxaliplatin) and three with API2 to target AKT activity. Tumor growth and metastasis progression were analyzed by positron emission tomography (PET). Results: Patient-derived cells generated tumor xenografts that recapitulated the same histopathological and genetic features as the original patients' carcinomas.Weshow an 87.5% tumor take rate that is one of the highest described for implanted cells derived from colorectal cancer patients. Cecal injection generated primary carcinomas and distant metastases. Oxaliplatin treatment prevented metastasis and API2 reduced tumor growth as evaluated by PET. Conclusions: Our improved protocol for cancer cell engraftment has allowed us to build a rapidly expanding collection of colorectal PDX, annotated for their clinical data, gene expression, mutational, and histopathological statuses. We have also established a mouse model for metastatic colon cancer with patient-derived cells in order to monitor tumor growth, metastasis evolution, and response to treatment by PET. Our PDX models could become the best preclinical approach through which to validate new biomarkers or investigate the metastatic potential and drug-response of individual patients. © 2013 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)6787-6801
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
Publication statusPublished - 15 Dec 2013

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    Puig, I., Chicote, I., Tenbaum, S. P., Arqués, O., Herance, J. R., Gispert, J. D., Jimenez, J., Landolfi, S., Caci, K., Allende, H., Mendizabal, L., Moreno, D., Charco, R., Espín, E., Prat, A., Elez, M. E., Argilés, G., Vivancos, A., Tabernero, J., ... Palmer, H. G. (2013). A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells. Clinical Cancer Research, 19(24), 6787-6801. https://doi.org/10.1158/1078-0432.CCR-12-1740