Projects

Identifying drivers of treatment resistance in metastatic colorectal cancer

Colorectal cancer is one of the most common and lethal tumour types. Once it spreads, a patient only has a 12% chance of surviving five years or more as the disease moves into vital organs, like the liver. Metastatic colorectal cancer is responsible for 700,000 global deaths every year.

Current therapies are often unsuccessful against metastatic tumours, which frequently recur after treatment ends. Poor understanding of the different types of cells that exist in a tumour and the pathways they use to resist treatment is a major roadblock to better outcomes.

The aim of this project is to identify which metastatic tumour cells drive treatment resistance and post-treatment regrowth, and to characterise the mechanisms that allow them to do it. The ability to prevent post-treatment recurrence would dramatically improve patient survival. To do so, the team uses patient-derived tumour organoids from colorectal cancer liver metastases, transcribed barcodes enabling clonal tracking, single cell resolution RNAseq and ATAC eq analyses, and in vivo validation in orthotopic xenograft models.

Relationship between genomic instability, tumour cell plasticity and immune escape

An important feature of solid tumours is the compromised function of immune cells, which enables tumour progression and contributes to treatment failure. The tumour microenvironment is often remodelled to become immunosuppressive and clinical and experimental evidence suggests that aggressive tumour cells play an active role in fostering this process. Increased genomic instability, a recurrent feature in metastatic cells, would be expected to trigger a stronger anti-cancer immune response. However, genomically instable cancer cells frequently manage to bypass this issue and successfully evade the immune system, and mechanisms that underpin this apparent paradox are poorly characterised.

In this project we analyse the relationship between features of genomically instable cells and the ability of tumour cells to exhibit plasticity and evade killing immune cells. We genetically manipulate cell cycle checkpoints and cell plasticity regulators to characterise their functional and molecular impact on tumour/immune cell interactions, using in ex vivo co-culture models and orthotopic tumour grafts.

Developmental Ligand/Receptor interactions as drivers of cancer cell plasticity in colorectal and pancreatic cancers

The netrin -1/UNC5B developmental ligand/receptor pair, physiologically implicated in the guidance of axons during embryonic development, was recently shown to regulate Epithelial to Mesenchymal Transition (EMT) in gynaecological and skin tumours.

In collaboration with Patrick Mehlen and Agnes Bernet (CRCL and Netris Pharma, Lyon, France), our project aims to characterise cellular targets and molecular pathways involved in the regulation of cancer cell plasticity by netrin-1 and UNC5B in preclinical models of colon and pancreatic cancers (mice models, patient-derived tumour spheres and organoids), as well as in human tumour biopsies. We will also characterise the impact of a humanised monoclonal antibody that prevents the binding of netrin-1 to UNC5B receptors (NP137) on the plasticity and survival of colorectal and pancreatic tumours, and assess whether it opens further therapeutic avenues combining NP137 with other targeted agents.

Mechanisms of standard of care resistance and characterisation of new combination therapies against pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is the fifth cause of cancer-related death. The 5-year survival rate is only around 10% for patients with this disease. Most PDAC patients die from their disease within one year of diagnosis, owing to the inefficacy of current standard-of-care chemotherapy regimens and the development of treatment resistance. Despite advances in molecular oncology and novel targeted therapies, most patients who present with pancreatic ductal adenocarcinoma are not candidates for these targeted therapies and undergo generic chemotherapy with FOLFIRINOX or gemcitabine ± nab-paclitaxel.

In this project, we performed a genome wide CRISPR-Cas9 dropout screen under the selection of chemotherapy in patient-derived PDAC organoids to identify potential genes which, when disrupted, can confer enhanced sensitivity to FOLFIRINOX treatment.

Using patient-derived organoids, CRISP-Cas9 silencing, pharmacological characterisation and in vivo models of PDAC, we are now aiming to characterise the mechanism that enable some of the candidates identified above to affect chemotherapy response in PDAC and to validate the clinical relevance of these candidates. We will also establish whether these candidates represent viable targets, either as biomarkers to stratify patients more/less likely to respond to standard of care treatment, or for the development of combination therapy approaches with chemotherapy.