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 Rojas; Héctor G. Palmer

doi:10.1158/1078-0432.CCR-12-1740

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 language	English
Pages (from-to)	6787-6801
Journal	Clinical Cancer Research
Volume	19
Issue number	24
DOIs	https://doi.org/10.1158/1078-0432.CCR-12-1740
Publication status	Published - 15 Dec 2013

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10.1158/1078-0432.CCR-12-1740

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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

@article{3749313d16b144e5ae78a8ceeadf1969,

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

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. {\textcopyright} 2013 American Association for Cancer Research.",

author = "Isabel Puig and Irene Chicote and Tenbaum, {Stephan P.} and Oriol Arqu{\'e}s and Herance, {Jos{\'e} Ra{\'u}l} and Gispert, {Juan D.} and Jos{\'e} Jimenez and Stefania Landolfi and Karina Caci and Helena Allende and Leire Mendizabal and Debora Moreno and Ram{\'o}n Charco and Eloy Esp{\'i}n and Aleix Prat and Elez, {Maria Elena} and Guillem Argil{\'e}s and Ana Vivancos and Josep Tabernero and Santiago Rojas and Palmer, {H{\'e}ctor G.}",

year = "2013",

month = dec,

day = "15",

doi = "10.1158/1078-0432.CCR-12-1740",

language = "English",

volume = "19",

pages = "6787--6801",

journal = "Clinical Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

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Puig, I, Chicote, I, Tenbaum, SP, Arqués, O, Herance, JR, Gispert, JD, Jimenez, J, Landolfi, S, Caci, K, Allende, H, Mendizabal, L, Moreno, D, Charco, R, Espín, E, Prat, A, Elez, ME, Argilés, G, Vivancos, A, Tabernero, J, Rojas, S & Palmer, HG 2013, 'A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells', Clinical Cancer Research, vol. 19, no. 24, pp. 6787-6801. https://doi.org/10.1158/1078-0432.CCR-12-1740

TY - JOUR

T1 - A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells

AU - Puig, Isabel

AU - Chicote, Irene

AU - Tenbaum, Stephan P.

AU - Arqués, Oriol

AU - Herance, José Raúl

AU - Gispert, Juan D.

AU - Jimenez, José

AU - Landolfi, Stefania

AU - Caci, Karina

AU - Allende, Helena

AU - Mendizabal, Leire

AU - Moreno, Debora

AU - Charco, Ramón

AU - Espín, Eloy

AU - Prat, Aleix

AU - Elez, Maria Elena

AU - Argilés, Guillem

AU - Vivancos, Ana

AU - Tabernero, Josep

AU - Rojas, Santiago

AU - Palmer, Héctor G.

PY - 2013/12/15

Y1 - 2013/12/15

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-12-1740

DO - 10.1158/1078-0432.CCR-12-1740

M3 - Article

SN - 1078-0432

VL - 19

SP - 6787

EP - 6801

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 24

ER -

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

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