Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Given the importance of mutations in oncogenes and tumor suppressor genes, it has been widely assumed that the mere accumulation of mutations is the primary process to explain cancer incidence. However, cancer is predominantly a disease of aging, with its incidence remaining low until the fourth decade of life, undergoing exponential growth thereafter. Furthermore, cells carrying well-characterized oncogenic mutations can be found across normal human tissues, and can persist for decades without ever developing cancer. Our current understanding of what factors govern this decades-long latency and eventual failure in aged tissues are extremely limited. A compelling argument to describe this is tissue integrity in terms of its structure and function, both of which decline with age, and could explain differential fitness for cells harboring oncogenic mutations. Our ignorance of these tissue dynamic processes stems from our inability to perform in vivo analysis over such long- time frames in relevant mouse models. We hypothesize that chronic liver disease (CLD) can be understood as an accelerated aging of the liver that similarly alters the fitness landscape, promoting the selection of mutated cells that progress towards hepatocellular carcinoma (HCC). We focused on CTNNB1 encoding for ß-catenin, as it is the most frequently mutated oncogene in human HCC, with ~30% of patients having alterations that render ß-catenin constitutively active. However, the precise mechanisms by which ß-catenin mutations drive HCC progression remain unknown. To address this knowledge gap, we have performed a long-term clonal lineage tracing of hepatocytes bearing Ctnnb1 activating mutations in both the normal and in the chronically injured liver. By coupling this tracing system with single cell RNAseq, we discovered that in the normal liver, ß- catenin mutated hepatocytes are incapable of undertaking a single cell division, but instead last for months in the tissue through a long process of cellular attrition and elimination, which we hypothesize is primarily attributed to ER stress and maladaptive UPR. Strikingly, in the context of CLD, we found that tissue injury unleashed the potential of ß-catenin mutated hepatocytes to clonally expand and drive the development of HCC tumors, solving a longstanding conundrum in the field. Importantly, using the same lineage tracing system, we found that ß- catenin mutated hepatocytes in normal livers of aged mice can similarly undergo clonal expansion as observed in CLD. In this proposal, we will investigate the specific molecular mechanisms that result in diminished cellular fitness of ß-catenin mutated hepatocytes in the normal liver and conversely, what mechanisms are behind the increase in cellular fitness of ß-catenin mutated hepatocytes during chronic liver damage. By focusing on these mechanisms, we expect to lay the groundwork for exploiting the vulnerabilities of ß-catenin mutated hepatocytes found in the normal liver while blocking the strengths they acquire during CLD to tackle this devastating disease.
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