HYDRA

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 post-surgical 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.
Circulating cell-free tumour DNA (ctDNA) measured in the blood of CC patients by liquid biopsies was recently shown to stratify patients without or with a micrometastatic residual disease (MRD), invisible by radioimaging, anticipating by several months the diagnosis of relapse. MRD classification of CC patients is performed in the clinical Units of the collaborative project as part of the large-scale randomized clinical trial SAGITTARIUS which aims to personalize the post-surgical care of early-stage CC based on MRD status. 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 three-dimensional (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 and repressive cis-regulators in MRD+ and MRD- tumors using integrated multi-omics in patient derived organoids (PDOs), (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 associated with the micrometastatic spread in PDOs and primary tumors by gene editing and spatial profiling at single-cell level. Maximising the potential of the expected outcomes the collaborative partnership has long-standing expertise in clinical trials of CC. This ensures that promising therapeutic targets 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.