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Role of bacterial LPS in colorectal cancer

A 2020/2021 Summer Studentship research project

Student: Jessica Permain
Supervisors: Dr Rachel Purcell, Dr Tamara Glyn
Sponsor: Cancer Society, Canterbury-West Coast Division

Introduction

Emerging evidence has shown strong links between the intestinal microbiome and colorectal cancer. It is believed the microbiome can induce immune response and modulate how tumours respond to treatments. Previous research from our lab has looked at a large colorectal cancer (CRC) cohort and found bacterial lipopolysaccharide (LPS) is a novel link between the microbiome and CRC development.

LPS from different bacteria have varying structures and can elicit different responses. We have previously shown LPS from Fusobacterium sp. is immunogenic, whilst LPS from Bacteroides fragilis is immunosuppressive in vitro LPS that is immunogenic may contribute to carcinogenesis by inducing methylation of DNA mismatch repair genes such as MLH1 and MSH2. Methylation of these genes result in MSI+ phenotype, in tumours which tend to respond favourably to immunotherapy.

This project aims to look at whether bacterial LPS can induce methylation of colorectal cancer cell lines, and the effect of this on the molecular landscape of the tumour.

Aim

This project could provide important preliminary data to explain why certain subtypes of CRC respond differently to immunotherapy, and how the tumour microbiome might influence this. This could direct subsequent preclinical studies involving the microbiome and CRC.

Method

The methodology will include cell culture, using HT 29 and HCT116 cell lines, and treatment with LPS extracted from different gram-negative bacteria, shown to be involved in CRC. Analysis of cytokines will be carried out using flow cytometry. Methylation analysis will be carried out using whole genome bi-sulphite sequencing and targeted methylation analysis of candidate genes, following LPS treatment. Bioinformatics analysis will be used to analyse methylation data.

Student researcher’s component of the study

The student will carry out all the laboratory-based experiments and bioinformatics analysis, with the guidance of an experienced bioinformatician.

Student prerequisites

Cell culture and flow-cytometry analysis would be an advantage.