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.

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.

Academic 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.

English Language Requirements

Applicants for whom English is not a first language will also require a minimum IELTS score of 6.5 (with 6.0 in the written component) or equivalent, unless your undergraduate degree was studied in, and awarded by, an English speaking country. For more information on acceptable English language qualifications please see here.

Fee Status

The funding for this studentship only covers tuition fees at the Home rate. Overseas applicants are welcome to apply, but will be required to fund the difference in tuition fees.

The studentship includes the following funding for 4 years:

• A tax-free annual stipend of £23,000
• Tuition fees at the Home rate*
• Project consumables

*If you are considered an Overseas student for fee purposes, you are welcome to apply for this studentship, however you will be required to cover the difference in tuition fees.

To apply you will need to complete an online application form. Please select the 'Non-Clinical PhD' option.

The following supporting documents will be required as part of your application:

• Your CV
• Statement of purpose
• Details of 2 referees
• Copy of your transcript(s), including a breakdown of marks
• Copy of your passport
• If applicable, proof of English proficiency

If you have a question about the project, or would like to arrange an informal discussion, please contact the supervisor directly (subject ‘PhD applicant’). For general enquiries about the PhD studentship or application process please contact the Teaching Office.

Successfully shortlisted candidates will be invited to an interview at Barts Cancer Institute.