Investigating intrinsic and extrinsic mechanisms driving plasticity in colorectal cancer metastasis

This CRUK-funded project will commence in September 2024 and has funding for 4 years. The successful candidate will be based at Barts Cancer Institute, Faculty of Medicine and Dentistry (FMD), Charterhouse Square in the City of London.

Colorectal cancer (CRC) is the third most common malignancy globally and one of the leading causes of cancer-related death because of its high relapse rate. A major challenge for inhibiting metastasis is the ability of cancer cells to reversibly switch states in response to microenvironmental cues along the metastatic cascade. Phenotypic heterogeneity driven by plasticity is increasingly recognised as a driver of tumour progression, metastasis and therapy resistance in colorectal cancer.

Using a combination of single-cell multiomics and spatial transcriptomics data from primary and metastatic CRC patients, we have characterised the heterogeneous malignant and non-malignant cell states in CRC. Our analysis shows cell hierarchies reminiscent of those in normal tissues, with stem cells (LGR5) giving rise to transit amplifying progenitors which differentiate into distinct absorptive and secretory lineages. In addition, we have identified putative pro-metastatic states with a regenerative and inflammatory phenotype (Ogden et al, 2023, preprint), driven by transcription factors AP-1 and NF-κB. We also detected an intermediate population with a hybrid regenerative and stem cell phenotype, indicating phenotypic transitions between stem and pro-metastatic cells. Our spatial analyses show that these regenerative cells are enriched at the invasive edge of primary CRC and reside in an immunosuppressive niche in both primary CRC and in liver metastasis, surrounded by immune and stromal cells that sustain these cells.

In this project, we aim to investigate the intrinsic regulatory factors and extrinsic signals from the microenvironment driving transitions to pro-metastatic states in colorectal cancer using patient samples and patient-derived organoids. We will reconstruct evolutionary trajectories of each patient to determine how cells navigate transitions towards invasive pro-metastatic states using joint DNA/RNA data. We will also profile histone modifications to identify regulatory elements driving these transitions. To spatially map the malignant cell states and the tumour microenvironment and dissect the extrinsic signals promoting/restricting plasticity, we will integrate our multi-omics data with spatial Visium and Xenium (10x Genomics) data. We will test and validate our computational predictions by perturbing patient-derived organoids using gene editing tools and single-cell multiomics.

Training

The student will have extensive training in computational analysis of multiomics data. They will work with a postdoctoral researcher responsible for the organoid work and will have an opportunity be trained in tissue culture, 3D organoid culture and CRISPR gene editing if interested.

Entry Requirements

Candidates should hold (or be about to obtain) a minimum upper-second-class honours degree (or equivalent) in a relevant subject (such as computational biology, or molecular or cellular biology with a keen interest in computational analysis).

Preferably the candidate would also have (or be about to obtain) a master’s degree or have other extensive experience in research (such as through an industrial placement or working as a research assistant). Candidates with an interest in computational analysis of multiomics data are especially encouraged to apply.