High-throughput screening in colorectal cancer tissue-originated spheroids

Cancer Sci. 2019 Jan;110(1):345-355. doi: 10.1111/cas.13843. Epub 2018 Nov 20.

Abstract

Patient-derived cancer organoid culture is an important live material that reflects clinical heterogeneity. However, the limited amount of organoids available for each case as well as the considerable amount of time and cost to expand in vitro makes it impractical to perform high-throughput drug screening using organoid cultures from multiple patients. Here, we report an advanced system for the high-throughput screening of 2427 drugs using the cancer tissue-originated spheroid (CTOS) method. In this system, we apply the CTOS method in an ex vivo platform from xenograft tumors, using machines to handle CTOS and reagents, and testing a CTOS reference panel of multiple CTOS lines for the hit drugs. CTOS passages in xenograft tumors resulted in minimal changes of morphological and genomic status, and xenograft tumor generation efficiently expanded the number of CTOS to evaluate multiple drugs. Our panel of colorectal cancer CTOS lines exhibited diverse sensitivities to the hit compounds, demonstrating the usefulness of this system for investigating highly heterogeneous disease.

Keywords: 3D culture; cancer; heterogeneity; high throughput screening; organoid.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Drug Screening Assays, Antitumor / methods*
  • High-Throughput Screening Assays / methods*
  • Humans
  • Mice, Inbred NOD
  • Mice, SCID
  • Organoids / drug effects
  • Organoids / metabolism
  • Organoids / pathology
  • Spheroids, Cellular / drug effects*
  • Spheroids, Cellular / metabolism
  • Spheroids, Cellular / pathology
  • Whole Exome Sequencing
  • Xenograft Model Antitumor Assays / methods

Substances

  • Antineoplastic Agents