Cancer Stem Cell-Based Models of Colorectal Cancer Reveal Molecular Determinants of Therapy Resistance
Open accessAbstract
Colorectal cancer (CRC) therapy mainly relies on the use of conventional chemotherapeutic drugs combined, in a subset of patients, with epidermal growth factor receptor [EGFR]-targeting agents. Although CRC is considered a prototype of a cancer stem cell (CSC)-driven tumor, the effects of both conventional and targeted therapies on the CSC compartment are largely unknown. We have optimized a protocol for colorectal CSC isolation that allowed us to obtain CSC-enriched cultures from primary tumor specimens, with high efficiency. CSC isolation was followed by in vitro and in vivo validation, genetic characterization, and drug sensitivity analysis, thus generating panels of CSC lines with defined patterns of genetic mutations and therapy sensitivity. Colorectal CSC lines were polyclonal and maintained intratumor heterogeneity in terms of somatically acquired mutations and differentiation state. Such CSC-enriched cultures were used to investigate the effects of both conventional and targeted therapies on the CSC compartment in vivo and to generate a proteomic picture of signaling pathways implicated in sensitivity/resistance to anti-EGFR agents. We propose CSC lines as a sound preclinical framework to test the effects of therapies in vitro and in vivo and to identify novel determinants of therapy resistance. Significance: Colorectal cancer stem cells (CSCs) have been shown to be responsible for tumor propagation, metastatic dissemination, and relapse. However, molecular pathways present in CSCs, as well as mechanisms of therapy resistance, are mostly unknown. Taking advantage of genetically characterized CSC lines derived from colorectal tumors, this study provides an extensive analysis of CSC response to EGFR-targeted therapy in vivo and an overview of factors implicated in therapy response or resistance. Furthermore, the implementation of a biobank of molecularly annotated CSC lines provides an innovative resource for future investigations in colorectal cancer.
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Autophagy and cancer stem cells also contribute to resistance to EGFR target therapy.
“Autophagy and cancer stem cells (CSCs) also contribute to resistance to EGFR target therapy [18, 137].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [137]
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Cites
Fast and accurate short read alignment with Burrows-Wheeler transform
Li, H., & Durbin, R. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp324 · Cited by 58,607 · see citing works
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
Cingolani, P., Platts, A., Wang, L. L., Coon, M., Nguyen, T., Wang, L., Land, S. J., Lu, X., & Ruden, D. M. (2012) · Fly · doi:10.4161/fly.19695 · Cited by 11,816 · see citing works
A framework for variation discovery and genotyping using next-generation DNA sequencing data
DePristo, M. A., Banks, E., Poplin, R. E., Garimella, K. V., Maguire, J., Hartl, C., Philippakis, A., del Angel, G., Rivas, M. A., Hanna, M., et al. (2011) · Nature Genetics · doi:10.1038/ng.806 · Cited by 11,216 · see citing works
Signatures of mutational processes in human cancer
Initiative, A. P. C. G., Alexandrov, L. B., ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, PedBrain, I., Nik-Zainal, S., Wedge, D. C., Aparicio, S. A. J. R., Behjati, S., Biankin, A. V., et al. (2013) · Nature · doi:10.1038/nature12477 · Cited by 9,660 · see citing works
Comprehensive molecular characterization of human colon and rectal cancer
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11252 · Cited by 8,499 · see citing works
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
Cibulskis, K., Lawrence, M. S., Carter, S. L., Sivachenko, A., Jaffe, D. B., Sougnez, C. L., Gabriel, S., Meyerson, M. M., Lander, E. S., & Getz, G. A. (2013) · Nature Biotechnology · doi:10.1038/nbt.2514 · Cited by 4,838 · see citing works
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G. J., van Es, J. H., van den Brink, S., van Houdt, W. J., Pronk, A., van Gorp, J., Siersema, P. D., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.07.050 · Cited by 3,753 · see citing works
Organoid Models and Applications in Biomedical Research
Xinaris, C., Brizi, V., & Remuzzi, G. (2015) · The Nephron journals/Nephron journals · doi:10.1159/000433566 · Cited by 3,517 · see citing works
Prospective Derivation of a Living Organoid Biobank of Colorectal Cancer Patients
van de Wetering, M., Francies, H. E., Francis, J. M., Bounova, G., Iorio, F., Pronk, A., van Houdt, W., van Gorp, J., Taylor-Weiner, A., Kester, L., et al. (2015) · Cell · doi:10.1016/j.cell.2015.03.053 · Cited by 2,408 · see citing works
Hu, Y., & Smyth, G. K. (2009) · Journal of Immunological Methods · doi:10.1016/j.jim.2009.06.008 · Cited by 2,091 · see citing works
The quest to overcome resistance to EGFR-targeted therapies in cancer
Chong, C. R., & Janne, P. A. (2013) · Nature Medicine · doi:10.1038/nm.3388 · Cited by 1,055 · see citing works
Bertotti, A., Migliardi, G., Galimi, F., Sassi, F., Torti, D., Isella, C., Corà, D., Di Nicolantonio, F., Buscarino, M., Petti, C., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0109 · Cited by 939 · see citing works
Merlos-Suárez, A., Barriga, F. M., Jung, P., Iglesias, M., Céspedes, M. V., Rossell, D., Sevillano, M., Hernando-Momblona, X., da Silva-Diz, V., Muñoz, P., et al. (2011) · Cell Stem Cell · doi:10.1016/j.stem.2011.02.020 · Cited by 934 · see citing works
De Sousa E Melo, F., Wang, X., Jansen, M., Fessler, E., Trinh, A., de Rooij, L. P. M. H., de Jong, J. H., de Boer, O. J., van Leersum, R., Bijlsma, M. F., et al. (2013) · Nature Medicine · doi:10.1038/nm.3174 · Cited by 771 · see citing works
Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity
Vermeulen, L., Todaro, M., Melo, F. D. S. E., Sprick, M. R., Kemper, K., Pérez‐Alea, M., Richel, D. J., Stassi, G., & Medema, J. P. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0805706105 · Cited by 725 · see citing works
Self-citationTodaro, M., Gaggianesi, M., Catalano, V., Benfante, A., Iovino, F., Biffoni, M., Apuzzo, T., Sperduti, I., Volpe, S., Cocorullo, G., et al. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.01.009 · Cited by 717 · see citing works
Self-citationLiu, X., Jian, X., & Boerwinkle, E. (2013) · Human Mutation · doi:10.1002/humu.22376 · Cited by 580 · see citing works
Colorectal Cancer Stem Cells: From the Crypt to the Clinic
Zeuner, A., Todaro, M., Stassi, G., & Maria, R. D. (2014) · Cell stem cell · doi:10.1016/j.stem.2014.11.012 · Cited by 370 · see citing works
Self-citationKondo, J., Endo, H., Okuyama, H., Ishikawa, O., Iishi, H., Tsujii, M., Ohue, M., & Inoue, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1015938108 · Cited by 322 · see citing works
Distinct types of tumor-initiating cells form human colon cancer tumors and metastases
Dieter, S. M., Ball, C. R., Hoffmann, C. M., Nowrouzi, A., Herbst, F., Zavidij, O., Abel, U., Arens, A., Weichert, W., Brand, K., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.08.010 · Cited by 297 · see citing works
Karlsson, H., Fryknäs, M., Larsson, R., & Nygren, P. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.03.026 · Cited by 180 · see citing works
Acquired resistance to EGFR‐targeted therapies in colorectal cancer
Emburgh, B. O. V., Bianchi, A. S., Nicolantonio, F. D., Siena, S., & Bardelli, A. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.05.003 · Cited by 160 · see citing works
Cammareri, P., Scopelliti, A., Todaro, M., Eterno, V., Francescangeli, F., Moyer, M. P., Agrusa, A., Dieli, F., Zeuner, A., & Stassi, G. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3953 · Cited by 159 · see citing works
Self-citationFang, D. D., Kim, Y. J., Lee, C. N., Aggarwal, S., McKinnon, K. M., Mesmer, D., Norton, J., Birse, C. E., He, T., Ruben, S. M., et al. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605610 · Cited by 151 · see citing works
MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors.
Luraghi, P., Reato, G., Cipriano, E., Sassi, F., Orzan, F., Bigatto, V., De Bacco, F., Menietti, E., Han, M., Rideout, W. M., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2340-t · Cited by 146 · see citing works
Horst, D. A., Chen, J., Morikawa, T., Ogino, S., Kirchner, T., & Shivdasani, R. A. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3222 · Cited by 128 · see citing works
Shapiro, G. I., Bell‐McGuinn, K. M., Molina, J. R., Bendell, J. C., Spicer, J. F., Kwak, E. L., Pandya, S. S., Millham, R., Borzillo, G. V., Pierce, K. J., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1306 · Cited by 123 · see citing works
Ohata, H., Ishiguro, T., Aihara, Y., Sato, A., Sakai, H., Sekine, S., Taniguchi, H., Akasu, T., Fujita, S., Nakagama, H., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-3812 · Cited by 106 · see citing works
Proliferation State and Polo-Like Kinase1 Dependence of Tumorigenic Colon Cancer Cells
Francescangeli, F., Patrizii, M., Signore, M., Federici, G., Franco, S. D., Pagliuca, A., Baiocchi, M., Biffoni, M., Ricci‐Vitiani, L., Todaro, M., et al. (2012) · Stem Cells · doi:10.1002/stem.1163 · Cited by 59 · see citing works
Self-citationDynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer
Francescangeli, F., Contavalli, P., Angelis, M. L. D., Baiocchi, M., Gambara, G., Pagliuca, A., Fiorenzano, A., Prezioso, C., Boe, A., Todaro, M., et al. (2015) · Cell Death and Differentiation · doi:10.1038/cdd.2015.19 · Cited by 57 · see citing works
Self-citationColorectal cancer-derived tumor spheroids retain the characteristics of original tumors
Lee, S. H., Hong, J. H., Park, H. K., Park, J. S., Kim, B., Lee, J.-Y., Jeong, J. Y., Yoon, G. S., Inoue, M., Choi, G., et al. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.06.024 · Cited by 54 · see citing works
Rajčević, U., Knol, J. C., Piersma, S. R., Bougnaud, S., Fack, F., Sundlisæter, E., Søndenaa, K., Myklebust, R., Pham, T. V., Niclou, S. P., et al. (2014) · Proteome Science · doi:10.1186/1477-5956-12-39 · Cited by 54 · see citing works
New models for cancer research: human cancer stem cell xenografts
Baiocchi, M., Biffoni, M., Ricci‐Vitiani, L., et al. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.05.002 · Cited by 50 · see citing works
Self-citationReverse Phase Protein Arrays: Mapping the Path Towards Personalized Medicine
Gallagher, R. I., & Espina, V. A. (2014) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-014-0122-3 · Cited by 41 · see citing works
D’Arcangelo, M., Todaro, M., Salvini, J., Benfante, A., Colorito, M. L., D’Incecco, A., Landi, L. M., Apuzzo, T., Rossi, E., Sani, S., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125037 · Cited by 16 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- 12 DePristo MA, Banks E, Poplin R et al. A frameworkforvariationdiscoveryandgenotyping using next-generation DNA sequencing data. Nat Genet 2011;43:491 -498.
Cited by
Sorted by citations
Zhou, J., Ji, Q., & Li, Q. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02130-2 · Cited by 246 · see citing works
Viel, A., Bruselles, A., Meccia, E., Fornasarig, M., Quaia, M., Canzonieri, V., Policicchio, E., Urso, E. D., Agostini, M., Genuardi, M., et al. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.022 · Cited by 217 · see citing works
Self-citationManic, G., Signore, M., Sistigu, A., Russo, G., Corradi, F., Siteni, S., Musella, M., Vitale, S., De Angelis, M. L., Pallocca, M., et al. (2018) · Gut · doi:10.1136/gutjnl-2016-312623 · Cited by 98 · see citing works
Self-citationBuikhuisen, J. Y., Gomez Barila, P. M., Torang, A., Dekker, D., de Jong, J. H., Cameron, K., Vitale, S., Stassi, G., van Hooff, S. R., Castro, M. A. A., et al. (2021) · Cancers · doi:10.3390/cancers13040801 · Cited by 33 · see citing works
Self-citationThe Impact of Cancer Stem Cells in Colorectal Cancer
Radu, P., Zurzu, M., Tigora, A., Paic, V., Bratucu, M., Garofil, D., Surlin, V., Munteanu, A. C., Coman, I. S., Popa, F., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25084140 · Cited by 30 · see citing works
Cell Therapy as Target Therapy against Colon Cancer Stem Cells
Garza Treviño, E. N., Quiroz Reyes, A. G., Rojas Murillo, J. A., de la Garza Kalife, D. A., Delgado Gonzalez, P., Islas, J. F., Estrada Rodriguez, A. E., & Gonzalez Villarreal, C. A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098163 · Cited by 24 · see citing works
- Authors
- De Angelis, M. L., Zeuner, A., Policicchio, E., Russo, G., Bruselles, A., Signore, M., Vitale, S., De Luca, G., Pilozzi, E., Boe, A., Stassi, G., Ricci-Vitiani, L., Amoreo, C. A., Pagliuca, A., Francescangeli, F., Tartaglia, M., De Maria, R., & Baiocchi, M.
- Affiliations
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Istituto Superiore di Sanità (IT)
- Sapienza University of Rome (IT)
- University of Palermo (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
- Istituto Nazionale Tumori Regina Elena, Rome, Italy
- Corresponding author
- Baiocchi, Marta
- ORCID
- Venue
- Stem Cells Translational Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-03-08
- Volume
- 5
- Issue
- 4
- Pages
- 511-523
- ISSN
- 2157-6564 (ISSN-L)
- 2157-6580
- PMC
- PMC4798739
- OpenAlex
- W2295718866
- Cited by
- 60
- References
- 36
- Citations by year
- 2026: 8 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 3 · 2018: 4 · 2017: 12 · 2016: 2
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells Translational Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nd)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
- Funders
- Italian Association for Cancer Research (15749)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- colorectal cancer, cancer stem cells, treatment resistance, anti-EGFR therapy, intratumoral heterogeneity, somatic mutations, drug sensitivity, proteomic profiling, signaling pathways, preclinical models, biobanks
- MeSH terms
- Animals, Cells, Cultured, Female, Humans, Mice, Transgenic, Models, Biological, Neoplastic Stem Cells, Colorectal Neoplasms, Signal Transduction, Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Gene Expression Profiling, Proteomics, Microarray Analysis, Protein Kinase Inhibitors
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