Investigating Transcript Diversity as a Driver of Melanoma Progression and Recurrence
Abstract
Melanoma is a highly metastatic cancer, however despite decades of research into how melanoma cells spread from primary tumors to other tissues, our ability to predict which patients will ultimately relapse, and options to prevent this, remain limited. Clearly new and creative approaches are required to solve this problem. As melanoma cells metastasize, they undergo a series of cell state transitions that allow them to invade the surrounding tissue, enter the circulatory system before colonizing distant organs. Exposure to these distinct environments in the body requires the ability to adapt, therefore understanding the molecular features of the distinct stages of melanoma progression is key to unlocking biomarkers and therapies to prevent metastasis. We will apply a powerful new technology to melanoma patient samples to identify new molecular pathways that influence metastatic spread that can be targeted to inhibit melanoma earlier in disease progression to prevent metastasis and increase melanoma patient survival. Thus, our proposal is aligned with the fiscal year 2022 (FY22) Melanoma Research Program (MRP) Challenge Statement and addresses the FY22 MRP Focus Area: Delineate the molecular pathways that influence metastatic spread, recurrence, and/or dormancy. Ultimately, we aim to discover new biomarkers and preventative therapeutics to stop melanoma in its tracks earlier and prevent recurrence. Scientific rationale: Human cells contain approximately 20,000 genes in the DNA, and these genes contain the information required to make proteins, the cell’s action molecules and building blocks. Intriguingly, there are many more proteins in our cells than there are genes, which helps explain the complexity of humans compared to simpler organisms that contain a similar number of genes. This diversity in proteins is produced by a mechanism called RNA processing or splicing. So, how does this work? First, a copy of the DNA comprising a single gene is made. This molecular copy of the gene is called messenger RNA (mRNA), and this contains the information needed to make a protein. However, the mRNA molecule can be processed in multiple ways, whereby pieces are removed, and new pieces joined together, ultimately generating variations in the original genetic code such that multiple proteins can be produced from the one gene. Critically, over 90% of human genes are processed in this way, yet when the functions of genes and proteins are tested, traditionally we only consider a single version of the mRNA and protein. Therefore, changes in mRNA diversity largely remains a hidden layer of cell regulation. This process seems important in cancer, because 30% more mRNA processing events occur in cancer cells compared to normal cells, and in some cases, the degree of mRNA diversity can predict patient outcome. Despite these initial observations, how changes in mRNA diversity relates to cancer progression, particularly from primary to metastatic disease, remains unexplored. To investigate this further, we need to understand how mRNA is processed in complex tumor ecosystems across distinct stages of progression. Thus, for this initiative we will apply a new and rapidly evolving sequencing technology, that provides superior resolution of mRNA processing than previously available methods, to primary and early metastatic melanoma patient samples. The advantage of this technology is that full-length mRNA molecules can be identified, which we have not been able to achieve previously. Therefore, the full degree of mRNA diversity can be detected for the first time. The main objectives of this proposal are to determine the relationship between global changes in mRNA diversity and metastasis in melanoma patients, and to determine whether specific mRNA variants are predictive of melanoma progression, and if these can be targeted to prevent melanoma metastasis. Outcomes: By sequencing full length mRNA molecules, we will identify
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310934
Entities
People
- Lorey Smith
Organizations
- United States Army
- University of Melbourne