Tuft Cells in the GI Cancer Microbiome: Unraveling their Role in Microbial Regulation
Supervisors: A/Prof Michael Buchert, Prof Matthias Ernst
Laboratories: Cancer and Inflammation Laboratory
Until recently, it was common to think that tumours are simply masses of a patient’s own cells that malfunction and grow uncontrollably when they, in fact, are communities of many different cell types. New research has now shown that tumours also play hosts to a collection of other life-forms entirely – microorganisms such as bacteria and fungi, some of which thrive in the environment around the tumour while others live inside the tumour cells themselves. Until recently it was unknown what roles these microbes play in tumours, however novel findings show that they can either assist or oppose tumour development and progression. For example, bacteria can protect the tumours by inactivating chemotherapy drugs or altering the ability of the immune system to target and destroy tumour cells, while other bacteria protect the body from tumour growth by detoxifying carcinogens or reducing levels of harmful reactive oxygen molecules that can damage DNA. This area of cancer microbiology is an emerging and exciting topic of research and promises to lead to new approaches for treating and preventing cancers.
Tuft cells (TCs) are a rare chemosensory epithelial cell type in the gastrointestinal (GI) tract and sole source of epithelial interleukin (IL) 25. TCs have an important function as immune sentinels in the epithelium that relay danger signals to the mucosa-resident immune cells in order to maintain a healthy tissue. Recently, TCs were shown to detect the presence of certain microbial metabolites and to induce the expression of IL13 in cells of the innate immune system which in turn altered the expression profile of antimicrobial peptides (AMPs) in epithelial cell types such as Paneth and goblet cells which led to changes in the composition of the mucosal microbiota. Moreover, treatment of mice with IL25 alone was sufficient to induce similar changes to the microbiota in the absence of microbial metabolites. Thus, TCs can sense and regulate the makeup of the resident microbial communities.
The aim of this PhD project is to investigate whether TCs inside or outside of the tumour tissue are involved in the regulation of the tumour-associated microbiota. We will use preclinical GI tumour models where we can specifically ablate TCs either in the tumour or in the unaffected surrounding healthy tissue and determine the abundance and composition of microbial communities by 16S RNA sequencing. We will further complement these experiments by pharmacologically blocking the activity of IL25 and IL13 in vivo. Lastly, we will determine the impact of both genetic and pharmacologic approaches on the ability of the host immune system or chemotherapy treatments to limit tumour growth.
The project will provide the candidate with the opportunity to work in cancer microbiology, an emergent and exciting new area of cancer research. Basic training in immunology/microbiology or cancer biology (Honours or Masters minimum) will be required.
Techniques involved:
- Flow cytometry
- Immunofluorescent microscopy
- 16S RNA sequencing
Recommended reading:
- The microbiome and human cancer. Science. 2021 Mar 26;371(6536)
- Tuft cells mediate commensal remodeling of the small intestinal antimicrobial landscape. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23)
- Cross talk between Paneth and tuft cells drives dysbiosis and inflammation in the gut mucosa. Proc Natl Acad Sci U S A. 2023 Jun 20;120(25)