Title: Elucidating The Mechanisms Of Cell Competition And Its Role In Tumour Biology To Identify Novel Anti-Cancer Strategies
Funder: Cancer Research UK

Abstract: • Background Tumour-host interactions play an increasingly recognized role in modulating tumour growth. Thus, understanding the nature and impact of this complex bidirectional communication is key to identify novel successful anti-cancer strategies. It has been suggested that tumour cells co-opt a form of cell interaction normally present in tissues, known as cell competition, to kill surrounding normal cells and clear space to fuel their expansion. Our recent work using Drosophila intestinal tumour models in fact shows that tumour and host tissues do compete, and that tumour cells must kill surrounding host cells in order to expand. This suggests that, by generating an environment permissive for tumour growth, cell competition acts as a key driver of tumourigenesis. Our work has further shown that if host cells surrounding the tumour are protected from tumour-host cell competition they can be empowered to contain tumour growth. Therefore understanding how to control cell competition and prevent cancer cells from killing surrounding host tissue may deliver novel unexplored anti-cancer strategies entirely complementary to those that have been and are currently being developed that target the tumour itself. • Aims The purpose of this research is two-fold: to advance our understanding of the mechanisms of cell competition and to investigate the relevance of cell competition to cancer, so as to power its use for therapeutic purposes. • Methods To achieve these objectives we will combine work in Drosophila with approaches using mammalian cells in culture and experiments testing the relevance of our findings in mouse pre-cancer models. Specifically, we will: 1) Carry out a targeted screen in Drosophila to identify, among a list of ~400 genes upregulated in loser cells, those involved in cell competition. 2) Investigate the molecular mechanisms of mechanical cell competition, a novel mode of cell competition that we have discovered in mammalian MDCK cells and that is induced by the tumour-suppressor p53. 3) Test the relevance of newly identified cell competition genes (emerging from points 1 and 2) to tumor-host cell competition using Drosophila intestinal tumour models. 4) Investigate the existence of tumour-host cell competition in vivo in mammals by intravital imaging, using mouse p53 mutant precancerous skin lesions. • How the results of this research will be used If successful this research will identify novel strategies to contain tumour growth and new drug targets that interfere with tumour growth by disrupting tumour-host cell competition.

Lay abstract: • Background Tumour-host interactions play an increasingly recognized role in modulating tumour growth. Thus, understanding the nature and impact of this complex bidirectional communication is key to identify novel successful anti-cancer strategies. It has been suggested that tumour cells co-opt a form of cell interaction normally present in tissues, known as cell competition, to kill surrounding normal cells and clear space to fuel their expansion. Our recent work using Drosophila intestinal tumour models in fact shows that tumour and host tissues do compete, and that tumour cells must kill surrounding host cells in order to expand. This suggests that, by generating an environment permissive for tumour growth, cell competition acts as a key driver of tumourigenesis. Our work has further shown that if host cells surrounding the tumour are protected from tumour-host cell competition they can be empowered to contain tumour growth. Therefore understanding how to control cell competition and prevent cancer cells from killing surrounding host tissue may deliver novel unexplored anti-cancer strategies entirely complementary to those that have been and are currently being developed that target the tumour itself. • Aims The purpose of this research is two-fold: to advance our understanding of the mechanisms of cell competition and to investigate the relevance of cell competition to cancer, so as to power its use for therapeutic purposes. • Methods To achieve these objectives we will combine work in Drosophila with approaches using mammalian cells in culture and experiments testing the relevance of our findings in mouse pre-cancer models. Specifically, we will: 1) Carry out a targeted screen in Drosophila to identify, among a list of ~400 genes upregulated in loser cells, those involved in cell competition. 2) Investigate the molecular mechanisms of mechanical cell competition, a novel mode of cell competition that we have discovered in mammalian MDCK cells and that is induced by the tumour-suppressor p53. 3) Test the relevance of newly identified cell competition genes (emerging from points 1 and 2) to tumor-host cell competition using Drosophila intestinal tumour models. 4) Investigate the existence of tumour-host cell competition in vivo in mammals by intravital imaging, using mouse p53 mutant precancerous skin lesions. • How the results of this research will be used If successful this research will identify novel strategies to contain tumour growth and new drug targets that interfere with tumour growth by disrupting tumour-host cell competition.

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