Investigating the role of tumour-associated macrophages in therapy response of colorectal cancer metastasis
Primary supervisor: Mirjana Efremova, Queen Mary University of London
Secondary supervisor: Tony Ng, King’s College London
Project
Combination chemotherapy regimes remain the most common treatment for colorectal cancer liver metastases. However, a large proportion of patients are unresponsive or experience disease recurrence, resulting in 5-year survival of less than 20%. One mechanism underlying therapy failure is plasticity, allowing cells to acquire a reversible drug-tolerant state and survive treatment. Following treatment, drug-tolerant cells can revert back to a proliferative state, highlighting their reversibility and the importance of monitoring over time.
Our analysis of single-cell RNA-seq and spatial transcriptomics data from patient samples shows extensive phenotypic heterogeneity of the cancer cell states, including two pro-metastatic regenerative and inflammatory states. Comparison of chemotreated and naïve samples revealed upregulation of signatures of regeneration and in particular inflammation in treated samples, alongside enrichment of pro-inflammatory tumour-associated macrophages (TAMs). We find similar signatures upregulated in chemotreated patient-derived organoids (PDOs) which then revert back to stem-like cells at recovery. However, how the crosstalk between cancer cells and macrophages evolves following chemotherapy in CRC liver metastasis remains poorly understood, limiting our capacity to halt therapeutic resistance. Reprogramming TAMs into an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy.
In this project, we aim to investigate the role of tumour-associated macrophages in the response of chemotherapy. Specifically:
- Investigate the effect of chemotherapy on tumour-associated macrophages.
We will establish PDOs co-cultured with pro-inflammatory TAMs derived from patient blood and tissue samples and following treatment with chemotherapy, we will profile them using both bulk and paired single-cell multiomics (RNA+ATAC). To decipher cellular heterogeneity and dynamic changes of TAMs after treatment, we will generate longitudinal data, considering treatment-naive, after treatment and at recovery.
- Investigate the effect of chemotherapy-induced inflammation on cancer cells.
To elucidate chemotherapy-induced dynamic changes in malignant cell states in presence of pro-inflammatory macrophages, we will use our longitudinal single-cell multiomics data to determine how chemotherapy modulates cancer cell phenotypes and how this differs in monoculture vs co-culture.
- Determine epigenetic regulators driving drug-tolerance and resistance promoted by chemotherapy-induced inflammation.
Drug-tolerant traits in cancer cells are increasingly recognised as being mediated by epigenetic regulatory processes, which enable a reversible, non-genetic form of resistance that allows a subpopulation of cells to survive therapeutic stress. To investigate the regulatory processes driving response and recovery, we will identify TFs that regulate drug-tolerant states induced after treatment as well as potentially more resistant cancer cell states at recovery. To validate these results, TF binding and changes in the deposition of histone activation and repressive marks will be characterised using CUT&RUN. We will then use inhibitors of relevant TFs and other factors and/or epigenetic knockdown using CRISPRi to dissect the biological mechanisms through which these drivers promote drug tolerance and resistance.
Candidate background
This project is highly multidisciplinary and would suit candidates with a background in molecular biology techniques, experience with organoid work and an interest in working with single-cell genomics data.
Potential Research Placements
- Tony Ng, Comprehensive Cancer Centre, King’s College London
- Özgen Deniz, Barts Cancer Institute, Queen Mary University of London
- Fran Balkwill, Barts Cancer Institute, Queen Mary University of London