Deciphering non-genetic determinants and targetability of cancer cell plasticity.

ongoing

Introduction Cancer cell plasticity, the ability of cancer cells to change their identity, enables tumors to adapt to hostile environments, aiding metastasis and resistance to treatments. Hence, plasticity is a major unsolved problem frustrating effective treatment. Unraveling the mechanisms underlying cancer cell plasticity is crucial to establish new avenues for cancer therapy. In contrast to adult cancers, many pediatric tumors are driven by a single genetic alteration that fuels their aggressive nature through remarkable plasticity. Despite their differences, pediatric cancers offer a unique platform to investigate cancer cell plasticity due to their genetically clear characteristics. I hypothesize that plasticity can be reversed to differentiate tumor cells and “mature cancer”. Goal Building upon previous ERC-StG funding, we have successfully utilized organoid technology, single-cell genomics, and lineage tracing approaches to uncover the origins of various pediatric cancers. Our findings revealed that these cancers exhibit robust yet pharmacologically reversible plasticity at the level of the epigenome. The goal of this proposal is to reverse cell state changes during tumorigenesis to “mature cancer”. Approach We will I) apply advanced (spatial) single-cell transcriptomics and epigenomics approaches to a unique cohort of pediatric tumors and metastases to map out cell state changes during disease progression, II) utilize our unique pediatric cancer organoids to interrogate and target hierarchical trajectories with the aim to mature cancer, and III) screen the enhancer-ome to identify non-genetic determinants of cancer cell plasticity. Innovation Integrating these cutting-edge technologies on patient-derived tissues and organoids will uncover fundamental principles governing cancer cell plasticity. The research will pioneer innovative methodologies and reveal strategies for identifying cancer maturation targets, advancing cancer therapy research