Pro-senescence therapies for basal-like breast cancer

Pro-senescence therapies trigger a cell cycle arrest halting tumour growth. The lack of targeted therapies for Basal-like breast cancer (BLBC) makes this aggressive cancer an excellent candidate for pro-senescence approaches. We have used 2D, high-throughput phenotypic screening to discover pro-senescence therapeutics for BLBC combined with genome-wide siRNA screening [1] to identify pro-senescence targets. We aim to use 3D cell systems that mimic the tumor microenvironment to probe the mechanism of action of these novel compounds, to explore the consequences of pro-senescence within the tumour microenvironment and neighbouring healthy cells, and to further develop 3D screening platforms for pro-senescence therapies.

Pro-senescence therapies are an exciting route to targeted therapy for cancers with an unmet clinical need such as BLBC [2]. The recent advent of 3D bioprinting has revolutionised the research and drug discovery landscape [3]. These 3D systems can:
1. faithfully recapitulate native cellular physiology;
2. provide invaluable mechanistic insights into cancer biology, e.g. by determining how drugs influence normal and diseased cells; and
3. enable scientists to unite this amenable technology with powerful screening platforms for drug discovery.

This ambitious and multidisciplinary PhD programme is made up of three, interwoven aims.

Aim 1. Determine the mechanism of action of pro-senescence compounds using 3D BLBC models
Phenotypic screening for drug discovery has uncovered novel pro-senescence compounds. We will determine the efficacy of these compounds in 3D BLBC models and probe how the top compounds act to trigger cancer cell senescence, exploiting our candidate pro-senescence targets in mechanistic studies.

Aim 2. Determine the impact of senescent cancer cells on the tumour microenvironment and surrounding healthy cells
Senescent cells secrete a cocktail of pro-inflammatory molecules, termed the senescence secretory phenotype (SASP) [4], which could potentially 'uncloak' cancer cells and trigger anti-tumour defenses. However, the SASP of senescent cancer cells is virtually unexplored. Therefore, we will investigate the consequence of cancer cell SASP factors within the tumour microenvironment and, importantly, their impact on surrounding healthy mammary fibroblasts and epithelial cells in 3D bioprinted co-culture models using matrigel.

Aim 3. Build a high-throughput 3D co-culture screening platform for pro-senescence drug discovery
In parallel, 3D bioprinting approaches will be expanded to generate high-throughput co-culture models of cancer and healthy cells for translational research. This will develop a phenotypic screening platform which simultaneously enables drug discovery (in cancer cells) and drug safety testing (in healthy fibroblast and epithelial cells) using human 3D co-culture models.