Scale up of organoid culture for their widespread use as a polarity model


Supervising PIs

Trevor Dale & Marianne Ellis

Project Description

Objectives

  • Analysis of cancer-induced changes in cell polarity using biophysically-purified organoid subpopulations.
  • Design and analysis of a device for biophysical purification of organoids.

Methodology

Recent studies showing cancer organoids recapitulate the biology of primary cancers have driven tremendous excitement in the potential for cancer organoids to revolutionise drug discovery and personalized medicine. At present, freshly-prepared organoids from colorectal cancers are composed of genetically and phenotypically diverse populations. Tumour heterogeneity at the genetic and phenotypic level drives differential responses to therapeutic agents. Differences in cell polarity / differentiation within multicellular cancer organoids underlies their differential drug responses. In this project, chemical engineering / bioreactor technologies will be used to separate distinct organoid subpopulations based on their size, shape and density. Purified populations of organoids will be used to study differences in organoid subtypes, function and polarity, and to relate genetic and phenotypic differences back to drug response and primary tumour heterogeneity. The outputs of this cross-disciplinary project will be 1. The development of a novel biophysical technique for the isolation of multicellular organoid subtypes. 2. The identification of genetic and phenotypic / cell polarity differences predict intra-tumour heterogeneity in response to therapeutics.

Collaborators

Key Publications

  1. Meneghello G, Storm MP, Chaudhuri JB, De Bank PA, Ellis MJ. An investigation into the stability of commercial versus MG63-derived hepatocyte growth factor under flow cultivation conditions. Biotechnol Lett. 2015 Mar;37(3):725–31.
  2. Shipley RJ, Davidson AJ, Chan K, Chaudhuri JB, Waters SL, Ellis MJ. A strategy to determine operating parameters in tissue engineering hollow fiber bioreactors. Biotechnol Bioeng. 2011 Jun;108(6):1450–61.
  3. Jardé T, Evans RJ, McQuillan KL, Parry L, Feng GJ, Alvares B, et al. In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89β-catenin system. Oncogene. 2013 Feb 14;32(7):883–93.
  4. Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz M-J, et al. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Oct 26