Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis

项目总结

PROJECT SUMMARY The transcription factor p53 is one of the most critical barriers to tumorigenesis. p53 is mutated in over half of all human tumors, and p53-mutant tumors typically carry a worse prognosis. As a tumor suppressor, p53 appears to act at the transition from benign to malignant disease, preventing transformation of cells that have already acquired some pro-tumor features, such as oncogene activation or DNA damage. Decades of research have sought to identify what makes p53 a potent tumor suppressor, as such knowledge could inform effective strategies for cancer prevention and treatment. This research has shown that p53 can be activated by a variety of signals, and in turn activated p53 can regulate a wide variety of cellular processes, including cell survival, senescence, genomic stability, and plasticity. However, the inducers and actions of p53 vary with context, and there is still no consensus on what signals engage p53 during early neoplasia and what biological programs are most important for its tumor-suppressive functions. Furthermore, we still do not know the key events following p53 loss that enable transition to malignancy. Attempts to gain this knowledge have been hampered by a lack of tools to directly study p53 in the specific cells undergoing transformation within endogenous contexts. To address these gaps in knowledge, we will study the events surrounding p53 activation and loss during the initiation of pancreatic ductal carcinoma (PDAC), an aggressive cancer in which p53 loss—which occurs in 70% of PDACs—enables progression from benign precursor lesions to full-blown cancer. We recently developed new mouse models of PDAC that allow us to “see” p53 in action as cells progress through the benign-to-malignant transition. Among the premalignant pancreas cells, we discovered a subpopulation that shares many transcriptional features with established tumor cells, and thus these cells appear to be transitioning from premalignant to malignant. These transitioning cells are also the cells with the strongest p53 activation, and so they provide a unique opportunity to study p53 engagement and tumor-suppressive function at the benign-to-malignant transition. Using single-cell transcriptional and spatial analyses, new computational approaches to infer cell state transitions, and our well-established platform for rapid genetic perturbations in vivo, we will define the cell-intrinsic and cell-extrinsic events that lead to this p53-active transitioning cell state. Furthermore, we will investigate the mechanisms by which activated p53 suppresses neoplastic transformation in the transitioning cells, as well as the events that influence cancer initiation immediately following p53 loss. This project will provide novel insight into the mechanisms that drive PDAC initiation and provide a direct and detailed characterization of p53 in action in endogenous contexts. Given the high prevalence of TP53 mutations in human cancers, we expect the insights into tumorigenesis to be applicable to many cancer types.