Grant: Project Grant

Cancer cells growing in solid tumors face a critical challenge: they outgrow their blood supply, creating regions of severe oxygen deprivation (hypoxia). While normal cells would die under these conditions, cancer cells adapt and survive, making hypoxic tumors highly aggressive and resistant to therapy. We have discovered a molecular 'oxygen sensor' that cancer cells hijack to survive in low-oxygen environments. This sensor is controlled by a protein called FLCN (folliculin), which normally acts as a tumor suppressor-its loss causes hereditary kidney cancer. We found that when oxygen levels drop, cells modify FLCN through a chemical tag called phosphorylation, turning off its tumor-suppressing function. This allows cancer cells to activate survival programs including recycling of cellular components (autophagy) and energy production, enabling them to thrive despite oxygen starvation. Our research aims to exploit this dependency: by blocking the pathways that hypoxic tumor cells rely on, we can selectively kill cancer cells in oxygen-deprived tumor regions while sparing normal tissues. This work will identify new drug targets and therapeutic strategies specifically designed to eliminate the most dangerous, treatment-resistant cells in breast cancer.