Michal Hershfinkel, PhD
Project Title
Silencing ZnR/GPR39-dependent signaling reduces cancer cell metastasis
About the Investigator
I earned my PhD in Physics and subsequently transitioned to physiology, where I discovered the zinc-sensing receptor ZnR/GPR39. This receptor is central to my research on the physiological roles of zinc. My lab elucidated the cellular pathways that ZnR/GPR39 activates and its impact on physiological functions. We specifically linked ZnR/GPR39 activity to enhanced wound healing, reduced diarrhea and modulation of saliva ion content that regulates taste sensitivity. I am a founding member of the International Society of Zinc in Biology and served as its president, I published more than 130 scientific papers that have more than 8000 citations.
About the Research
Therapy resistance and invasiveness challenge treatment of aggressive cancers like estrogen receptor-negative breast cancer and glioblastoma (GBM). Our lab discovered that ZnRGPR39 drives breast cancer cell growth and invasion by triggering calcium signals, inducing protrusion (lamellipodia) growth for cellular movement, and activating extracellular matrix breakdown (via MMP2/9). Analysis of expression databases indicates that high ZnRGPR39 levels are associated with poor patient survival across cancers including breast, brain, lung, liver, and pancreas. In this project we propose to establish tools for silencing ZnRGPR39 as cancer therapy. We will first establish ZnR/GPR39 as a regulator of multiple cancer cells growth and determine its role in migration and invasion. We will then design molecular tools to silence ZnR/GPR39 (CRISPR knockout and shRNA) and validate if durable silencing reduces invasion in cell models. Finally, we will package these silencing tools in lipid nanoparticles (LNPs) selectively targeted for cancer cells and use mouse tumor models (breast/brain xenografts) to test how ZnR/GPR39 silencing affects tumor growth and metastasis. Together, these studies will deliver a platform for silencing ZnR/GPR39, a previously unexploited driver of highly malignant tumors, with clear potential for clinical strategies in patients with therapy-resistant disease.
