Combining CRISPR-screens and AI to Identify Novel Therapeutic Strategies to Target Cancer-Stroma Interactions

As tumours progress, the relationship between cancer cells and the tumour microenvironment (TME) evolves to promote growth and evade anti-tumour immunity. This multidisciplinary project will combine the fields of cancer biology, bioinformatics and artificial intelligence to identify tractable targets for manipulating the cancer-TME interaction for clinical translation. This requires the development of new methodologies capable of modelling fundamental biological mechanisms."

During tumorigenesis, malignant phenotypes evolve along with molecular susceptibilities that can be targeted by therapies. Initiatives like the cancer dependency map (DepMap) aim to systematically unravel these vulnerabilities through extensive loss-of-function (CRISPR) screens across cancer cell lines. However, these studies are not performed in a microenvironment that is representative of a patient cancer and focus solely on cancer cells themselves.

This project will address this limitation by exploring strategies to target the interactions between cancer, stromal and immune cells.

Working with colleagues from the BCI and Exscientia, a leading AI drug discovery company, you will integrate in-house and publicly available genome-wide CRISPR screen, proteomic and transcriptomic datasets. To delineate novel targetable pro-tumourigenic pathways, you will apply cutting-edge machine learning methods to construct interpretable models of cancer-stroma-immune interactions.

Your computational predictions will be tested by colleagues in the Cameron laboratory in state-of-the-art 3D heterotypic co-cultures that accurately mimic TMEs. Results from lab experiments will feed a prediction-validation learning loop, ensuring the continual improvement of computational models and resulting target predictions. Promising new targets with the potential to impede tumour progression and manipulate the immune suppressive microenvironment will be exploited in concert with Exscientia's AI-driven target identification, prioritization and drug design capabilities.