Team Julie PANNEQUIN

Tumor recurrence and metastasis are the leading causes of colorectal cancer (CRC) mortality, affecting nearly half of patients within 5-y after curative-intent therapy. Relapsed CRC may initially go undetected by standard surveillance, highlighting the need for enhanced monitoring to identify patients with post-treatment minimal residual disease (MRD). Circulating tumor DNA (ctDNA) measured by liquid biopsies is a promising non-invasive approach for continuous follow-up of patients with higher sensitivity than conventional imaging, enabling better detection of tumor dormancy, relapse and therapeutic resistance. Yet, its analysis is extremely challenging due to low fraction of tumor-derived cell-free DNA, and consensus on its clinical validity in CRC is currently lacking. Despite advances, current gold-standard next-generation sequencing (NGS) still shows limited sensitivity, especially in post-treatment remission. Additionally, it is resource-intensive and not always clinically accessible.

Here, our main goal is to improve the detection of CRC progression and recurrence by developing a minimally invasive, personalized and cost-effective monitoring strategy based on multimodal ctDNA analysis from a single blood sample. By exploiting the potential of third-generation nanopore-based sequencing, our approach aims to increase the sensitivity of ctDNA detection, especially when present at minimal levels after treatment (MRD), which can be considered a marker of early recurrence and therapeutic resistance.

To achieve this goal, the project includes:

• The use of mouse models for modelling clinical patterns of tumor progression and therapeutic resistance
• The use of CRC samples from patient plasma and tissue biopsies
• The development of computational methods for multimodal analysis of ctDNA from nanopore sequencing data