Research

Heterocellular Signalling in CRC

The human body contains around 40 trillion cells comprising hundreds of different cell types. This complex ‘heterocellularity’ enables metazoan tissues to achieve multiple phenotypes from an isogenic genome. For example, in the human colon, intestinal epithelial cells control nutrient uptake, whereas stromal fibroblasts support epithelial renewal, and tissue-resident macrophages patrol against infection. This multicellular collaboration requires different cell types to communicate.

Like healthy tissue, cancer also contains lots of different cell types. For example, colorectal cancer (CRC) tumours contain mutated epithelial cells, stromal fibroblasts, and multiple immune cells. Each of these cell types contribute to CRC, but the signalling mechanisms underpinning their malignant behaviour are poorly-understood.

The Cell Communication Lab studies how cancer cells communicate with stromal and immune cells in CRC. By understanding how cancer cells regulate all cell types within a tumour, we aim to uncover novel approaches to treat cancer.

Research Projects:

1. Microenvironmental Regulation of Personalised Drug Responses

Each patient’s tumour is a unique ecosystem of interacting cell-types. We have previously demonstrated that cancer associated fibroblasts (CAFs) can protect cancer cells from chemotherapy in a patient-specific manner (Ramos Zapatero et al., Cell, 2023). CAFs can polarise cancer cells to from a chemosensitive proliferative colonic stem cell (proCSC) to a slow-cycling revival colonic stem cell (revCSC) fate that enables cancer cells to withstand chemotherapy-induced DNA-damage and cell-cycle blockage.

To explore how the tumour microenvironment regulates personalised drug responses at scale, we have now established TAILOR (Treatment Analysis via Individualised Organoid Responses). TAILOR combines a large UCLH CRC patient-derived microenvironment (PDM) organoid model biobank with custom single-cell phenotyping technologies (Qin et al., Nature Methods, 2020 and Sufi & Qin et al., Nature Protocols, 2021) to understand how autologous tumour microenvironment cells regulate personalised therapy responses.

2. Cancer Plasticity Phenoscaping

Although CRC is widely considered to be a genetically driven disease, non-genetic plasticity has recently been shown to drive tumour initiation, metastasis, and therapy response in CRC. Through perturbation analysis of >1,000 organoid cultures, we have charted a single-cell phenoscape of colonic stem cell plasticity driven by cell-extrinsic cues and cell-intrinsic mutations (Qin & Cardoso Rodriguez et al., Cell, 2023).

We are now studying how combinations of cell-intrinsic mutations and cell-extrinsic stromal cues control colonic stem cell identity in CRC.

3. Cellular Therapy—Cancer Interactions

Adoptive T-cell therapies have revolutionised the treatment of haematological cancers but have yet to make an impact on solid tumours. Unlike chemical drugs, cellular therapies are living systems that vary from donor to donor and can undergo dynamic plasticity shifts when interacting with cancer cells.

By combining patient-derived organoid models with novel cellular therapies developed across the CRUK City of London Centre and high-throughout single-cell phenotyping, we are studying how T-cell therapy signalling can be reprogrammed by cancer cells. By understanding how cellular therapy signalling is regulated in a patient-specific manner, we aim to improve the performance of anti-solid tumour biotherapeutics.