IGNITION · Controlling cell lineage integrity to intercept tumor initiation

Human tissues can tolerate a series of mutations in tumor suppressors and oncogenes without necessarily transforming. Potential for tumor initiation is not only determined by such accumulated molecular defects but also by the capacity of each cell and tissue to deal with them. Intrinsic cell plasticity – i.e. the ability to change phenotypes by accessing alternative expression programs - appears to be one of the determining factors of the penetrance of oncogenic stresses. Yet, how cell plasticity contributes to tumorigenesis remains poorly understood, in part because we can hardly access tumor initiation in humans. With IGNITION, we propose to uncover mechanisms maintaining cell lineage integrity under oncogenic stress in humans and explore their therapeutic potential to delay tumor initiation. To do so, we propose to access tumor initiation in humans using samples from the standard of care of BRCA1/2 mutation carriers. We will reconstitute entire individual trajectories up to tumor initiation, taking advantage of our privileged access to bio-banked and fresh human samples through the Curie hospital. Serial sampling for individual patients will be paired to organoid avatars, to expand our ability to observe tumor initiation events. Combining high resolution single-cell transcriptomics and epigenomics, we will identify recurrent non-genetic determinants of tumor initiation and study their potential as breaks or accelerators of tumor initiation with Cas9/CRISPR approaches in organoid models. Finally, we will test two strategies for therapeutic intervention: (i) control cell lineage integrity by restraining plasticity of the epithelial cell compartments, or (ii) targeting predispositions to transformation. Our long-term goal is to build on this integrated appreciation of tumor initiation to propose therapeutic strategies to monitor and delay tumor initiation in patients with pre-disposition to cancer.