A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis

Cell Stem Cell. 2016 Jun 2;18(6):827-38. doi: 10.1016/j.stem.2016.04.003. Epub 2016 May 19.

Abstract

Colorectal tumor is a heterogeneous disease, with varying clinical presentation and prognosis in patients. To establish a platform encompassing this diversity, we generated 55 colorectal tumor organoid lines from a range of histological subtypes and clinical stages, including rare subtypes. Each line was defined by gene expression signatures and optimized for organoid culture according to niche factor requirements. In vitro and in xenografts, the organoids reproduced the histopathological grade and differentiation capacity of their parental tumors. Notably, we found that niche-independent growth is predominantly associated with the adenoma-carcinoma transition reflecting accumulation of multiple mutations. For matched pairs of primary and metastatic organoids, which had similar genetic profiles and niche factor requirements, the metastasis-derived organoids exhibited higher metastatic capacity. These observations underscore the importance of genotype-phenotype analyses at a single-patient level and the value of our resource to provide insights into colorectal tumorigenesis and patient-centered therapeutic development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Epidermal Growth Factor / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genetic Heterogeneity
  • Genome, Human
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation / genetics
  • Organoids / metabolism
  • Organoids / pathology*
  • Stem Cell Niche* / genetics
  • Transforming Growth Factor beta / metabolism
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Wnt Proteins / metabolism

Substances

  • Transforming Growth Factor beta
  • Wnt Proteins
  • Epidermal Growth Factor