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Tumor and Stem Cell Biology

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

Paolo Luraghi, Gigliola Reato, Elia Cipriano, Francesco Sassi, Francesca Orzan, Viola Bigatto, Francesca De Bacco, Elena Menietti, May Han, William M. Rideout III, Timothy Perera, Andrea Bertotti, Livio Trusolino, Paolo M. Comoglio and Carla Boccaccio
Paolo Luraghi
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Gigliola Reato
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Elia Cipriano
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Francesco Sassi
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Francesca Orzan
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Viola Bigatto
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Francesca De Bacco
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Elena Menietti
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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May Han
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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William M. Rideout III
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Timothy Perera
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Andrea Bertotti
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Livio Trusolino
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Paolo M. Comoglio
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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Carla Boccaccio
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
1Institute for Cancer Research at Candiolo (IRCC), Center for Experimental Clinical Molecular Oncology; 2Department of Oncology, University of Torino, Candiolo, Torino, Italy; 3Aveo Oncology Inc., Cambridge, Massachusetts; and 4Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
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DOI: 10.1158/0008-5472.CAN-13-2340-T Published March 2014
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Abstract

Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer–initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed “xenospheres,” were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts; like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, whereas those harboring wild-type RAS pathway genes (RASwt) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RASwt CCICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof-of-concept for concurrent targeting of these two pathways in the clinical setting. Cancer Res; 74(6); 1857–69. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received August 15, 2013.
  • Revision received December 9, 2013.
  • Accepted December 28, 2013.
  • ©2014 American Association for Cancer Research.
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Cancer Research: 74 (6)
March 2014
Volume 74, Issue 6
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MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
Paolo Luraghi, Gigliola Reato, Elia Cipriano, Francesco Sassi, Francesca Orzan, Viola Bigatto, Francesca De Bacco, Elena Menietti, May Han, William M. Rideout III, Timothy Perera, Andrea Bertotti, Livio Trusolino, Paolo M. Comoglio and Carla Boccaccio
Cancer Res March 15 2014 (74) (6) 1857-1869; DOI: 10.1158/0008-5472.CAN-13-2340-T

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MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors
Paolo Luraghi, Gigliola Reato, Elia Cipriano, Francesco Sassi, Francesca Orzan, Viola Bigatto, Francesca De Bacco, Elena Menietti, May Han, William M. Rideout III, Timothy Perera, Andrea Bertotti, Livio Trusolino, Paolo M. Comoglio and Carla Boccaccio
Cancer Res March 15 2014 (74) (6) 1857-1869; DOI: 10.1158/0008-5472.CAN-13-2340-T
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