Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance

M. L. De Angelis, A. Zeuner, E. Policicchio, Giorgio Russo, Alessandro Bruselles, Michele Signore, Sara Vitale, Gabriele De Luca, E. Pilozzi, Alessandra Boe, Giorgio Stassi, Lucia Ricci-Vitiani, Carla Azzurra Amoreo, Alfredo Pagliuca, Federica Francescangeli, Marco Tartaglia, Ruggero Marchiano De Maria, Marta Baiocchi

Research output: Contribution to journalArticle

Abstract

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.Wepropose 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.

Original languageEnglish
Pages (from-to)511-523
Number of pages13
JournalStem cells translational medicine
Volume5
Issue number4
DOIs
Publication statusPublished - 2016

Keywords

  • Anti-EGFR therapy
  • Cancer stem cells
  • Cetuximab
  • Colorectal cancer
  • Proteomic arrays

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology

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  • Cite this

    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. M., & Baiocchi, M. (2016). Cancer stem cell-based models of colorectal cancer reveal molecular determinants of therapy resistance. Stem cells translational medicine, 5(4), 511-523. https://doi.org/10.5966/sctm.2015-0214