Characterising the role of netrin-1 and its dependence receptors in drug tolerance and treatment-induced plasticity of metastatic human CRC

Colorectal cancer (CRC) is one of the most common and lethal tumour types worldwide. The ultimate cause of patient fatality is metastases forming in vital organs, such as the liver, as these tumours often relapse after treatment has ceased. A patient with metastatic CRC only has 12% chance of surviving, and each year metastatic progression leads to a fatal outcome for over 690,000 patients globally. Research to date has not provided an effective solution to post-treatment relapse for these patients.

We know that metastases often grow back after treatment stops due to cells that are capable of resisting or adapting to drug treatments within each tumour. More specifically, it has emerged that a key driver of recurrence is heterogeneous drug sensitivity among cell subpopulations within individual metastases, with some metastatic cells displaying enhanced plasticity and survival abilities in response to treatment. The recent literature suggests that expression of Epithelial-to-Mesenchymal Transition (EMT) correlates with therapy resistance and that post-treatment residual disease often displays mesenchymal and tumour-initiating features. Indeed, recent unpublished results from the Australian partner indicate that colorectal cancer liver metastases that resist treatment with the standard of care chemotherapy Folfox display highly enriched EMT characteristics. Of interest, netrin-1 and its receptors DCC/UNC5B have been shown to be very important in colorectal tumorigenesis and very recent unpublished data support the view that the pair netrin-1/UNC5B is instrumental in regulating tumoral EMT (Lengrand et al., in preparation). Moreover, an anti-netrin-1 antibody, disrupting the interaction between netrin-1 and UNC5B have been transferred to the clinic and has shown some very promising signs of activity in patients with advanced solid tumors (ESMO 2019) with in term of biological effect a demonstrated effect on reversing EMT when comparing biopsies of patients before and during treatment.

While we know that intra-tumour heterogeneity is instrumental in the ability of tumour cell subpopulations to escape therapy, no data exist on the implication of netrin-1 and its receptors in this process. Poor understanding of intra-metastatic heterogeneity and of the pathways metastatic cells can use to resist treatment is a major roadblock. To refine our knowledge of these processes, it is essential to investigate them at the cellular/clonal level rather than to analyse population-wide responses.

Our Project: Our project aims to shift this roadblock by identifying which metastatic tumour cells drive post-treatment regrowth and by characterising the mechanisms underlying this ability. Taking advantage of the combined expertise of the Australian and French partners, we will characterize the emerging role of the netrin-1/UNC5B axis as a driver of drug tolerance and cancer cell plasticity.

Supervisors:

The University of Melbourne: Prof Frederic Hollande.

CNRS: Dr Patrick Mehlen.