Xiaojun Roger Shi, PhD, a Case CCC Molecular Oncology Program member has received a five-year, $1.7 million R01 grant from the National Institute of General Medical Sciences (NIGMS) to investigate the molecular mechanisms regulating EphA2, a cell-surface receptor implicated in cancer progression and metastasis.
Shi, an assistant professor at Case Western Reserve University School of Medicine and MetroHealth Medical Center, received the award in July 2026, two years after establishing his independent laboratory.
EphA2 is a receptor tyrosine kinase frequently overexpressed in solid tumors and associated with tumor invasion, metastasis and therapeutic resistance. Depending on its signaling state, EphA2 can either promote or suppress malignant behavior. Understanding the mechanisms governing these opposing functions could inform more selective therapeutic approaches.
The funded project, “Mechanistic Insight into Conformational Regulation of EphA2: From Structure to Function,” builds on Shi's previous research published in Science, which identified distinct molecular interactions underlying EphA2's opposing signaling functions.
Shi will use molecular simulations, advanced fluorescence techniques and cell-based assays to investigate how structural changes in EphA2's extracellular region regulate intracellular kinase activity. Preliminary findings suggest a potential molecular switch involved in receptor activation.
“Our research seeks to understand how the structure of cell-surface receptors determines their biological functions,” said Shi. “EphA2 is particularly intriguing because the same receptor can either promote or suppress cancer progression. By uncovering the structural mechanisms governing these opposing functions, we hope to lay the groundwork for more precise therapeutic strategies.”
The research aims to identify mechanisms that could enable selective inhibition of cancer-promoting EphA2 signaling while preserving its tumor-suppressive functions.