Title: Mechanisms of attenuated Salmonella cancer therapy–metabolic reprogramming and immune modulation
Funder: Cancer Research UK

Abstract: Background One of the key aims in finding new cancer treatments is to specifically target tumour tissue, while leaving normal tissue untouched. Bacterial cancer therapy (BCT) is exciting because attenuated bacteria can do just that, they can home specifically to tumours using nutrient sensing-pathways and can survive within tumours for long periods and induce tumour regression. Yet the mechanisms of BCT are poorly defined, which thus limits their advance to into clinical use. I have been studying mechanisms of BCT using an attenuated Salmonella typhimurium strain in in situ mouse models of intestinal cancer and have found rapid and robust metabolic reprogramming, transcriptional changes in stem cell and epithelial-mesenchymal transition markers, and significant tumour regression. These findings warrant further investigation, which I aim to establish my research group around. Aims This project will; 1: dissect how attenuated Salmonella treatment alters the tumour metabolic environment, 2: determine the best treatment regimen and potentiation of co-therapies, 3: test efficacy on human colorectal cancers in vitro and understand mechanisms and 4: determine the effect of attenuated Salmonella treatment on immunocyte infiltration and function in the altered metabolic environment. Methods This project will use mouse models of colorectal and intestinal cancer; AOM/DSS-induced colitis associated cancer (CAC) and Apcmin/+ mice (model of human familial adenomatous polyposis, FAP). Mice developing tumours in these models will be treated with attenuated Salmonella typhimurium (STmaroA) and tumour growth analysed by endpoint analysis and also endoscopy (for the CAC model). In vivo work will be coupled with in vitro culture of tumour organoids derived from the mouse models and from human primary tumours. Human tumour organoids will be sequenced so we can map efficacy of STm to tumour subtypes. Analysis of the different models will involve metabolomics (LC-MS), Mass Spectrometry imaging, transcriptional analysis including single cell RNA sequencing, bacterial sequencing, immunohistochemistry and flow cytometry for immunophenotyping. How the results of the research will be used This project will determine how efficient attenuated Salmonella treatment is over time, gain a better understanding of the mechanisms of tumour regression and describe the best treatment regime in the mouse models. We will also determine the efficacy of attenuated Salmonella on human colorectal cancer organoids. This work should enable us to better define patients/cancer types that would potentially benefit from such treatment and inform on how to set up treatment regimens; from the choice of bacteria, to timing of administration and potential co-therapies.

Lay abstract: Background One of the key aims in finding new cancer treatments is to specifically target tumour tissue, while leaving normal tissue untouched. Bacterial cancer therapy (BCT) is exciting because attenuated bacteria can do just that, they can home specifically to tumours using nutrient sensing-pathways and can survive within tumours for long periods and induce tumour regression. Yet the mechanisms of BCT are poorly defined, which thus limits their advance to into clinical use. I have been studying mechanisms of BCT using an attenuated Salmonella typhimurium strain in in situ mouse models of intestinal cancer and have found rapid and robust metabolic reprogramming, transcriptional changes in stem cell and epithelial-mesenchymal transition markers, and significant tumour regression. These findings warrant further investigation, which I aim to establish my research group around. Aims This project will; 1: dissect how attenuated Salmonella treatment alters the tumour metabolic environment, 2: determine the best treatment regimen and potentiation of co-therapies, 3: test efficacy on human colorectal cancers in vitro and understand mechanisms and 4: determine the effect of attenuated Salmonella treatment on immunocyte infiltration and function in the altered metabolic environment. Methods This project will use mouse models of colorectal and intestinal cancer; AOM/DSS-induced colitis associated cancer (CAC) and Apcmin/+ mice (model of human familial adenomatous polyposis, FAP). Mice developing tumours in these models will be treated with attenuated Salmonella typhimurium (STmaroA) and tumour growth analysed by endpoint analysis and also endoscopy (for the CAC model). In vivo work will be coupled with in vitro culture of tumour organoids derived from the mouse models and from human primary tumours. Human tumour organoids will be sequenced so we can map efficacy of STm to tumour subtypes. Analysis of the different models will involve metabolomics (LC-MS), Mass Spectrometry imaging, transcriptional analysis including single cell RNA sequencing, bacterial sequencing, immunohistochemistry and flow cytometry for immunophenotyping. How the results of the research will be used This project will determine how efficient attenuated Salmonella treatment is over time, gain a better understanding of the mechanisms of tumour regression and describe the best treatment regime in the mouse models. We will also determine the efficacy of attenuated Salmonella on human colorectal cancer organoids. This work should enable us to better define patients/cancer types that would potentially benefit from such treatment and inform on how to set up treatment regimens; from the choice of bacteria, to timing of administration and potential co-therapies.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS