APOBEC3A Drives Tumor Evolution and Intratumoral Heterogeneity in PDAC
Abstract
Pancreatic cancers are very aggressive and nearly always lethal. Pancreatic tumors have had very many changes to their DNA, leading to very complex genomes. They tend to spread to other body parts early on and typically do not respond well to therapy. Changes to the DNA occur in nearly all cancers and are important in cancer development. They also lead to drug resistance, and tumor spread to other parts of the body, which is the most important cause of death in pancreatic cancer patients. Large studies investigating the DNA of cancer have identified specific enzymes that can modify DNA, called APOBEC cytidine deaminases, as important players that lead to many changes in DNA and, therefore, they are likely very important in the development of multiple cancers, including pancreatic cancer. These APOBEC enzymes can create differences between different cells that make up the cancer, and these differences allow the most aggressive cancer cells to survive and grow, in a process similar to Darwin s evolution of species. This can increase the cancer s ability to spread to other parts of the body, as well as its ability to evade cancer treatments. A3A is one of those APOBEC enzymes and has been identified as a key player in these processes. We have recently found that, in addition to this, A3A also plays a role in making large-scale changes to the cancer s chromosomes, which further accelerates early pancreatic tumor lesions to develop into aggressive pancreatic cancers, and also makes the tumors more aggressive and able to spread to other parts of the body. However, to really understand these processes, we need to decipher the exact role A3A plays in creating differences between cancer cells, and exactly which chromosomal changes A3A makes and how this impacts the early and late stages of pancreatic cancer evolution and its spread to other parts of the body. We hypothesize that A3A s role of making both small-scale changes to the cancer s DNA and large-scale chromosomal changes, leads to differences between cancer cells and allows more aggressive cancer cells to develop, playing a key role in pancreatic cancer aggressiveness and spreading to other parts of the body. If we could, in the future, develop medicines that could block A3A, that would be a very promising approach to help us prevent pancreatic cancers from developing, becoming aggressive, and spreading to other body parts. The overarching goal of this proposal is to show that A3A can be used to predict how pancreatic cancers develop and progress to become aggressive and spread to other parts of the body. This would indicate that A3A would be a very promising target that medicines can be developed against, leading to better outcomes for pancreatic cancer patients. This project addresses two fiscal year 2022 Pancreatic Cancer Research Program Focus Areas: (1) Understanding precursors, origins, and early progression of pancreatic cancer, and (2) Understanding the events that promote pancreatic cancer metastasis. We focus on understanding the mechanistic underpinnings of changes to the DNA in cancer cells and differences between cancer cells, both of which promote the early development and progression of pancreatic cancers (precursors, origins, and early progression), as well as the spread of pancreatic cancers to other parts of the body (metastasis). Our proposal is innovative on several fronts: (1) To the best of our knowledge, this will be the first study that will use engineered animal models of A3A, as well as its variant A3AE72A (which is unable to cause small changes to the DNA), to investigate the role of A3A in creating differences between cancer cells, in causing small-scale DNA changes and large-scale changes to the cancer s chromosomes, and in tumor development and in spreading to other parts of the body. (2) In addition, we believe this is the first time that small-scale and large-scale changes to the DNA caused by A3A will be studied a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310855
Entities
People
- Sonja Woermann
Organizations
- Rechts der Isar Hospital
- United States Army