Exploring mechanisms of apoptotic regulators in normal and malignant biology
The proteins that control normal homeostasis are often corrupted to drive cancer cell survival. Our laboratory studies the function of BCL-2 family proteins, particularly MCL-1. Projects encompass normal and malignant biology, and basic mitochondrial dynamics. Our goal is to better understand the survival cues that regulate development and function. Ultimately, we hope to uncover novel ways to exploit these signals to treat pediatric cancers.
Members of the BCL-2 family of molecules serve as critical regulators of cellular survival and death, playing important roles in controlling development, maintaining tissue homeostasis, and promoting the survival of malignant cells. Our laboratory investigates how individual BCL-2 family members regulate normal hematopoiesis and, when dysregulated, promote malignant cell survival. We employ a variety of cellular, genetic, and biochemical approaches to identify specific BCL-2 family proteins, their respective roles, and their feature in different systems.
A key area of research centers on the anti-apoptotic protein MCL-1, which is necessary to promote the survival of hematopoietic lineages and other tissues. In addition to its role on the outer-mitochondrial membrane where it inhibits cell death, we discovered that MCL-1 also localizes to the mitochondrial matrix where it promotes mitochondrial function and respiration. Our laboratory has a growing interest in mitochondrial signaling, energy production maintenance, and apoptosis regulation. Using transgenic models, we are conducting loss-of-function and gain-of-function studies to decipher the mechanisms that regulate mitochondrial metabolism. Similarly, genomic and metabolomic studies are shedding light on MCL-1's function in the mitochondria. Modeling the hematopoietic system in vivo allows us to explore stem cell self-renewal and regeneration following stress, and the functional aspects of how MCL-1 controls that process.
MCL-1 is among the most frequently amplified genes in adult cancers, and virtually all malignancies harbor alterations in apoptotic signaling. Identifying potential MCL-1, and other BCL-2 family, inhibitors is critical to improving treatment responses in malignancies including leukemia. Previous work from our laboratory revealed that many normal signaling pathways can modulate apoptotic sensitivity, and therefore, have potential applications in cancer therapy. We have developed tools to evaluate these so-called BH3 mimetics for potency, selectivity, and mechanism of action. We are particularly interested in how we can exploit the cellular signaling to improve the action of BH3-mimetic drugs in models of acute leukemia. CRISPR-Cas9-based genome wide screens facilitate our investigation of drug responses and how they trigger cell death.