On Aug. 30th, 2023, Mikhail A. Nikiforov, PhD, was awarded a new National Institutes of Health/National Cancer Institute Research Project Grant (NIH/NCI R01) titled “The Role of Regulation and Subcellular Localization of GTP Biosynthesis in Melanoma Invasion and Metastasis.” The $2.5 million funds will be dispersed annually over the next five years.
Subcellular localization is the process of assigning a protein sequence to one of four to sixteen compartments. Guanosine Triphosphate (GTP) is a nucleotide that is synthesized in cells through many processes. Acquisition of invasive phenotypes – and expression of cancer cells that determine whether a cancer will metastasize - is critical for the progression from primary to metastatic melanoma.
Invasive melanoma is the deadliest form of skin cancer that can spread to other parts of the body if left untreated. The process of invasion is a key step in the progression of benign melanocyte hyperplasia to life-threatening melanoma. Melanoma usually starts as a single tumor or lesion, and becomes metastatic as it spreads to distant locations.
Such progression is most detrimental for patient survival in case of melanoma brain metastases (MBMs). Invasion of melanoma cells depends on activation of several RHO-GTPases - molecular switches that control signal transduction pathways. These proteins regulate the biogenesis of cell protrusions, formation of which is essential for cancer cell invasion.
RAC1 is a protein found in human cells that is encoded by the RAC1 gene. Rac1 is a member of the Rho family of GTPases. Among RHO-GTPases, RAC1 plays the most prominent role in melanoma progression.
Nikiforov’s team discovered that enzymes that control metabolism of GTP regulate the activity of RHO-GTPases, including RAC1. This occurs via modulation of the local amounts of GTP in the vicinity of RAC1 or other RHO-GTPases. Furthermore, GTP metabolism enzymes interact with RAC1 and are enriched in cell protrusions. Therefore, the goal of Nikiforov’s research supported by current grant is to elucidate mechanisms recruiting GTP biosynthesis enzymes to cell protrusions - a critical part of cell function that are involved in many basic processes such as cell migration.
In this way, they hope to understand regulation of GTP biosynthesis in melanoma cells, and to test whether inhibition of GTP biosynthesis is a feasible strategy to treat MBM.
Over the past several years, Nikiforov has co-authored the following papers related to this research:
- Internally Ratiometric Fluorescent Sensors for Evaluation of Intracellular GTP Levels and Distribution (Nature Methods, Sept. 4, 2017)
- Regulation of Local GTP availability Controls RAC1 Activity and Cell Invasion (Nature Communications, Oct. 19, 2021)
- Phosphorylation of Guanosine Monophosphate Reductase Triggers a GTP-Dependent Switch from Pro- to Anti-Oncogenic Function of EPHA4 (Cell Chemical Biology, June 16, 2022)
Read more about the Nikiforov Lab’s research here.