Introduction

Although our understanding of molecular mechanisms that underpin the progression of colorectal cancers has greatly improved over the past 30 years, clinical benefits have been limited over the same period and very few novel therapies have emerged from this increased knowledge. A key reason is related to the notion of tumour plasticity, whereby phenotypic adaptability of tumour cells enables their resistance to current treatments. Tumour cell plasticity is supported by signals from the microenvironment, and the group of P. Mehlen has pioneered the field of dependance receptors, believed to act a tumour suppressors through their ability to induce cell death in specific micro-environmental contexts. F. Hollande’s group has developed integrated and clinically-relevant models enabling the analysis of tumour cell plasticity and our joint project will be to characterize the role of netrin-1 dependence receptors in the regulation tumour cell plasticity in colorectal and other digestive cancers.

Main objectives of research

Our main objectives will be, using tumour organoids and explants derived from liver metastases of tumours with patients with stage IV colorectal cancer, to longitudinally characterise the expression and activity of Dependence Receptors during exposure of metastatic colorectal cancer to standard of care chemotherapy and targeted therapy, in correlation with the phenotypic and molecular response of individual patient sample to these treatments. We will thereafter determine the role of dependence receptor activity in mechanisms that drive the overall resistance of non-responsive metastases or the recurrence process frequently observed in metastases that exhibit an initial response to treatment.  Finally, we will characterise target cell populations, molecular mechanisms (EMT, apoptotic pathways…) involved in these effects and propose possible therapeutic avenues to circumvent tumour cell plasticity in preclinical models.    

Network activities and expected results

Research activities under this IRP rely on the complementarity of French and Australian partners expertise, respectively in the field of dependence receptors and in the preclinical model generation and analysis of metastatic colorectal cancer. 

Specific results from this project will enable the characterisation of molecular mechanisms that drive the plasticity and treatment resistance of metastatic tumour cells, the determination of dependence receptor pathways best suited to therapeutic targeting in this cancer, and the preclinical validation of this strategy to prevent recurrence after treatment with standard of care chemotherapy.

 In addition, both partners plan to engage with colleagues in their respective centres (Lyon Cancer Research Centre in France, Victorian Comprehensive Cancer Centre in Australia) to create additional synergies between researchers and clinicians enabling the facilitation of technology, student/staff and data transfer for the benefit of cancer patients.

Institutions and laboratories involved

France

• CRCL – CNRS 5286 -INSERM UMR 1052 

Australia

• University of Melbourne Centre for Cancer Research, Tumour Heterogeneity in Metastatic Cancer Laboratory.  

Example of patient-derived tumour organoids grown from liver metastasis samples of patients with stage IV CRC (courtesy M. Brisset, Hollande Lab)

Increased apoptotic response in metatastic colorectal cancer organoids after treatment targeting the interaction between Netrin-1 and its dependence receptors, in comparison with organoids without treatment or treated with a control antibody.

From Yan Sun et al., Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2103319118.

Correlation between the expression of Netrin-1 and the N-terminal p53 isoform Δ40p53Δ40p53 in human melanoma and colorectal tumor biopsies.