Control of cellular self-digestion in lung tumorigenesis
Initial Award Abstract
Lung cancer, the most common cause of cancer-related death in men and the second most common in women, is responsible for 1.3 million deaths worldwide annually. If diagnosed early when the disease is surgically removable, chances of recovery are good, but once the cancer spreads, even aggressive chemotherapy is often ineffective. A need therefore exists to understand how lung cancer cells survive and how to more effectively kill them.
Our goal is to study the function of an anti-death protein named BI-1, which is frequently over-produced in lung cancers. BI-1 blocks cell death induced by stimuli that commonly occur in the middle of rapidly growing tumors, where cancer cells become starved of nutrients and oxygen. Autophagy is a process by which cells survive during times of nutrient deprivation, and we have found that BI-1 regulates this mechanism. Autophagy means “self eating”, representing a way for cells to degrade their internal components to generate a source of fuel and thus maintain critical levels of energetic molecules. In many lung tumors, genes involved in autophagy are mutated, suggesting that dysregulation of autophagy contributes to lung cancer development or progression. The combined findings that BI-1 is overproduced in lung tumors and that it also modulates autophagy have encouraged us to direct our studies towards understanding how BI-1 performs its functions and how we might advantageously apply this knowledge to improve lung cancer treatment. To address these questions, we will genetically manipulate lung cancer cells to either increase or decrease the levels of the BI-1 protein. With these engineered cells, we will then assess the impact of manipulating BI-1 levels on autophagy, cell survival, and tumorigenesis through a combination of cell culture and mouse tumor model experiments. We will also study the impact of BI-1 on responses of lung cancer cells to chemotherapeutic drugs.
Altogether, these investigations will help to elucidate novel mechanisms of autophagy regulation in lung cancer, while providing a window for potential application of new drugs that can target tumor cells. |