Colorectal cancer is a major cause of cancer-related death, with 30-40% of early-stage colon cancer (CC) patients relapsing with distant metastasis. Contrary to traditional models that view metastasis as a late event during tumor evolution, emerging concepts place the time of micrometastatic seeding long before radioimaging detection. This implies that the molecular drivers of metastatic propensity preexist in the primary tumor, yet none of the common risk classifiers robustly predicts the individual risk of relapse. In consequence, efficacious treatments or tailored follow-up strategies are lacking in the postsurgical care of patients and all CC patients receive a standard-of-care one-fits-all adjuvant chemotherapy which, however, fails to cure the majority of metastatic-prone cases and is iatrogenic for those that are not.
Circulating cell-free tumour DNA (ctDNA) measured in the blood of CC patients by liquid biopsy was recently shown to stratify patients with or without a micrometastatic residual disease (MRD), invisible to radioimaging, anticipating by several months the diagnosis of relapse. In this project, MRD classification of CC patients will be performed by the Clinical Units as part of the large-scale randomized clinical trial SAGITTARIUS which aims at personalizing the post-surgical care of early-stage CC based on presence of ctDNA. Capitalizing on this clinical platform, our goal is to explore and characterize the epigenomic mechanisms that reshape tumor cells fostering their metastatic divergence in phenotypically identical patients with differential MRD status detected by ctDNA and clinical data. Based on seminal findings from our teams, we posit that metastases, contrary to what generally thought, may be seeded years before diagnosis, and that this metastatic propensity is endowed through the rewiring of the primary tumor chromatin interactomes in threedimensional (3D) space. Unveiling the transcription factors (TF) that govern these metastasis-associated regulatory hubs in MRD+ versus MRD- tumors can highlight actionable targets of epigenomic deregulation for therapeutic intervention.
Our aims are to: i) characterize the active cis-regulators using integrated multi-omics in patient derived organoids (PDOs) from MRD+/- patients, ii) dissect the alterations in 3D genome topology that denote the molecular switch towards micrometastatic carcinoma by exploiting chromosome conformation capture assays, and iii) investigate the role of candidate TFs in PDOs by gene editing, and the MRD-associated signatures in primary tumors by spatial omics at single-cell resolution. Maximising the potential of the expected outcomes the collaborative partnership has long-standing expertise in clinical trials of CC. This ensures that promising findings can form the backbone of future studies investigating the clinical efficacy of therapeutics with important medical and socioeconomic benefits for the management of high-burden metastatic disease in CC.