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Dissecting microbiome and immune interactions in human intestinal (cancer) organoids

Objective

We pioneered the essential role of Wnt signals in adult stem cells, i.e. in intestinal crypts. We also found that loss of the APC gene activates the Wnt pathway and causes colorectal cancer (CRC). We then identified a Wnt target gene, Lgr5, which allowed us to define the crypt stem cells. In a previous ERC grant based on these findings, we identified novel Lgr5 stem cells in multiple organs, and defined in vitro culture conditions to grow epithelial organoids from single Lgr5 stem cells. Crucial in this was our identification of the Wnt agonistic R-spondins as the Lgr5 ligands. Cultured 'mini-guts' display all characteristics of normal gut, can be expanded for years, transplanted, and remain genetically stable.

Here, I propose a reductionist, ‘mini-gut’-based approach to two exciting research fields that currently mostly focus at the organismal/patient level: Microbiome research leans on deep-sequencing of complex microbial communities in health and disease; and immune checkpoint research in cancer rests largely on clinical trials of checkpoint-blocking antibodies. While many insights exist into the gut microbiome and -immune system, the epithelium is often treated as a neutral player. ‘Mini-gut’ technology allows us to dissect interactions of the gut microbiome with healthy and diseased epithelium, and of Tumor-Infiltrating Lymphocytes (TILs) with CRC 'mini-guts' (tumoroids).

To this end, we will describe/study
1) All immune receptors, -regulators and -effectors in the individual epithelial cell types.
2) 'Mini-guts' recombined with individual bacterial species,
3) CRC tumoroids recombined with their cultured TILs and subjected to immune checkpoint manipulation.
Using advanced molecular and imaging technologies, we will chart the molecular mechanisms that underlie the interactions from the ‘epithelial perspective’. Ultimately, this program will provide molecular detail to the effects of the microbiome and immune system on our gut, in health and disease.

Field of science

  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /medical and health sciences/basic medicine/immunology
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /medical and health sciences/clinical medicine/oncology/cancer/colorectal cancer

Call for proposal

ERC-2014-ADG
See other projects for this call

Funding Scheme

ERC-ADG - Advanced Grant

Host institution

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Netherlands
Activity type
Other
EU contribution
€ 3 062 438

Beneficiaries (1)

KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCHAPPEN - KNAW
Netherlands
EU contribution
€ 3 062 438
Address
Kloveniersburgwal 29 Het Trippenhuis
1011 JV Amsterdam
Activity type
Other