Charting Patient-specific Regulators of Plasticity in Primary and Metastatic Colorectal Cancer

Bowel cancer afflicts >900,000 people worldwide and is a major source of cancer-related mortality. While surgical resection of primary bowel tumours is occasionally curative, metastases in other organs such as the liver are responsible for residual disease and ultimately patient death. Existing bowel cancer chemotherapies target fast-growing cancer cells while sparing slow-growing cells. Unfortunately, new research has revealed that bowel cancer cells can rapidly change from fast-growing into slow-growing cells to escape chemotherapy. Such cellular 'plasticity' is now considered to be a fundamental feature of bowel cancer. Unfortunately we currently have no way to target plasticity to treat either primary or metastatic bowel cancer.
This MRC Research Grant will explore the inter- and intra-cellular signalling mechanisms controlling cellular plasticity in both primary and metastatic bowel cancer. Using a combination of patient-derived mini-tumour models (known as organoids) from primary and metastatic bowel cancer, novel high-throughput single-cell analysis technologies, and advanced computational methods, we will chart the cell-extrinsic and cell-intrinsic processes that regulate bowel cancer plasticity. Specifically, we will address the following research questions:

Question 1: What are the cell-extrinsic cues that regulate cellular plasticity and drug responses in primary and metastatic CRC and how do these vary across patients?
Question 2: How do cell-extrinsic cues signal via post-translational modifications (PTMs) to regulate gene expression programmes required for plasticity?
Question 3: How can we control patient-specific stem cell plasticity to improve therapeutic responses?

We will investigate these questions by integrating three novel technology platforms:
1) A cohort of x20 primary and x20 metastatic CRC patient-derived organoids (PDOs) from Memorial Sloan Kettering Cancer Centre (MSKCC) (Moorman et al., Nature, in press) and University College London...