Colorectal cancer spheroid biobanks: Multi-level approaches to drug sensitivity studies

M.L. De Angelis, A. Bruselles, F. Francescangeli, F. Pucilli, S. Vitale, A. Zeuner, M. Tartaglia, M. Baiocchi

Research output: Contribution to journalArticlepeer-review

Abstract

Biobanking of molecularly characterized colorectal cancer stem cells (CSCs) generated from individual patients and growing as spheroids in defined serum-free media offer a fast, feasible, and multi-level approach for the screening of targeted therapies and drug resistance molecular studies. By combining in vitro and in vivo analyses of cetuximab efficacy with genetic data on an ongoing collection of stem cell-enriched spheroids, we describe the identification and preliminary characterization of microsatellite stable (MSS) CSCs that, despite the presence of the KRAS (G12D) mutation, display epidermal growth factor (EGF)-dependent growth and are strongly inhibited by anti-EGF-receptor (EGFR) treatment. In parallel, we detected an increased resistance to anti-EGFR therapy of microsatellite instable (MSI) CSC lines irrespective of KRAS mutational status. MSI CSC lines carried mutations in genes coding for proteins with a role in RAS and calcium signaling, highlighting the role of a genomically unstable context in determining anti-EGFR resistance. Altogether, these results argue for a multifactorial origin of anti-EGFR resistance that emerges as the effect of multiple events targeting direct and indirect regulators of the EGFR pathway. An improved understanding of key molecular determinants of sensitivity/resistance to EGFR inhibition will be instrumental to optimize the clinical efficacy of anti-EGFR agents, representing a further step towards personalized treatments. © Springer Science+Business Media, LLC, part of Springer Nature 2018.
Original languageEnglish
Pages (from-to)459-469
Number of pages11
JournalCell Biology and Toxicology
Volume34
Issue number6
DOIs
Publication statusPublished - 2018

Keywords

  • Cancer stem cells
  • Cetuximab
  • Colorectal cancer
  • Personalized therapy
  • Spheroid cultures

Fingerprint Dive into the research topics of 'Colorectal cancer spheroid biobanks: Multi-level approaches to drug sensitivity studies'. Together they form a unique fingerprint.

Cite this