Identifying Mechanisms Initiating LAM and Angiomyolipoma in Tuberous Sclerosis Complex
Abstract
Tuberous sclerosis complex (TSC) is an inherited disease with a wide range of features and severity. The signs and symptoms of TSC include neurologic symptoms such as seizures, mental retardation, autism, and benign tumors in multiple organs including the brain, skin, lung (lymphangioleiomyomatosis), heart, and kidney (angiomyolipomas). TSC is a result of mutations in either of two genes, TSC1 or TSC2, resulting in constitutive activation of the mammalian target of Rapamycin (mTOR). Aberrant differentiation is a hallmark of TSC lesions, for instance, brain lesions contain "giant cells" that inappropriately co-express markers for neuronal and glial differentiation. This co-expression suggests a lack of terminal differentiation since only progenitor cells, but not terminally differentiated cells (i.e., neuron or glia), can express both markers. Similarly, lymphangioleiomyomatosis (LAM) and angiomyolipoma cells express smooth muscle and melanocytic markers, indicating a lack of terminal fate commitment. Markers expressed by LAM and angiomyolipoma cells and our preliminary studies suggest a neural crest origin for these lesions. The neural crest is a transient structure in the developing embryo formed by cells with multipotential and self-renewing capacity. This multipotent capacity allows neural crest stem cells to differentiate into a variety of cells including neurons and glial cells of the peripheral nervous system, melanocytes and smooth muscle cells. Notch family genes are expressed by neural crest cells and regulate their cell fate decisions. Since Notch inhibits neuronal differentiation and promotes a glial differentiation, one would predict that TSC cells with their co-expression of neuronal and glial markers have dysregulation of Notch signaling. Our long-term goal is to understand how neural crest and activation of Notch contributes to TSC pathogenesis with potential for the Notch pathway to be targeted for TSC patient therapy. We hypothesize that Rheb induces Notch activation within cells bearing mutated TSC1 or TSC2 genes. This Notch activation blocks the terminal differentiation of these cells and limits their capability to become terminally differentiated cells. As a result, LAM and angiomyolipoma cells have a neural crest pluripotent progenitor phenotype and enhanced survival. Thus, targeting Notch for TSC therapy will redirect TSC cell differentiation and limit survival of these cells. We hypothesize that combining Notch inhibition with other agents such as mTOR inhibitors will prove to be highly effective. Mouse models generated through this research will likely recapitulate TSC and other neural crest-derived malignancies such as melanoma; therefore, applications of this research are not limited to TSC. These mouse models have potential to serve as tools for preclinical studies of newly developed Notch inhibitors. Therefore, this project has significant therapeutic implications and may lead to new forms of therapy for TSC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510098
Entities
People
- Magdalena Karbowniczek
Organizations
- Texas Tech University Health Sciences Center
- United States Army