Selected Grantee Publications
Allelic Strengths of Encephalopathy-Associated UBA5 Variants Correlate Between In Vivo and In Vitro Assays
Pan et al., eLife. 2023.
https://pubmed.ncbi.nlm.nih.gov/37502976/
The UBA5 gene is associated with developmental and epileptic encephalopathy 44 (DEE44), an autosomal recessive disorder, in humans. The link between UBA5 variants and severity of DEE44, however, is not established. Investigators developed humanized fly models carrying a series of patient UBA5 variants. These flies showed differences in survival rates, developmental progress, life span, and neurological well-being. The severity of these defects correlated strongly with functional defects of UBA5 variants, allowing the classification of UBA5 loss-of-function variants into mild, intermediate, and severe allelic strengths in patients. This study provides resources for systematic investigation of the mechanistic link between UBA5 variants and DEE44 and for developing diagnostic approaches. Supported by ORIP (R24OD022005, R24OD031447, U54OD035865) and NCATS.
Host-Derived Growth Factors Drive ERK Phosphorylation and MCL1 Expression to Promote Osteosarcoma Cell Survival During Metastatic Lung Colonization
McAloney et al., Cellular Oncology. 2023.
https://pubmed.ncbi.nlm.nih.gov/37676378/
Mortality from osteosarcoma is closely linked to lung metastasis, even though the lung appears to be a hostile environment for tumor cells. Using female mice, researchers assessed changes in both host and tumor cells during colonization. Their findings suggest that the mitogen-activated protein kinase (MAPK) pathway is significantly elevated in early and established metastases, which correlates with expression of anti-apoptotic genes (e.g., MCL1). The authors conclude that niche-derived growth factors drive increased MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. This gene is a promising target for future therapeutic development. Supported by ORIP (K01OD031811), NCI, and NCATS.