Reciprocal interactions between apoptosis pathway and cell size

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The removal of unwanted cells through programmed cell death is critical for development and the maintenance of cellular homeostasis. Misregulation of programmed cell death can lead to disease, including cancer. Apoptosis is a type of programmed cell death that is conserved across animal species and that has been studied intensely over the past 30-40 years. These studies have resulted in the identification and characterization of a handful of factors that form the 'apoptosis pathway', which when activated in a cell, triggers apoptosis. These factors include pro- and anti-apoptotic Bcl-2-like proteins, Apaf-1-like proteins and caspases, enzymes that can cleave other proteins. It is the activation of these caspases above a critical 'lethal activity' threshold that triggers apoptosis. Importantly, our comprehensive understanding of the apoptosis pathway has led to the development of cancer therapeutics referred to as 'BH3 mimetics', which since 2016, have been used in the clinic to treat patients with chronic lymphocytic leukemia and other types of cancer. BH3 mimetics target anti-apoptotic Bcl-2-like proteins. However, challenges remain with BH3 mimetic-based treatments and these are toxicity and the development of resistance. These challenges reflect two shortcomings of our understanding of the apoptosis pathway. First, we are still lacking a comprehensive understanding of how the apoptosis pathway is controlled in vivo. Second, there is increasing evidence that the apoptosis pathway has functions other than in the removal of unwanted cells and we still lack sufficient knowledge of these 'non-canonical' functions. The proposed project addresses both of these shortcomings.It has been suggested that the size of a cell can trigger apoptosis. However, definitive evidence is lacking especially in vivo. The goal of Aim 1 is to investigate, in the context of animal development, the contribution of cell size to the activation of the apoptosis pathway. To that end, we will use the nematode Caenorhabditis elegans, a model organism that has been extensively used to study apoptosis. Indeed, a number of components of the apoptosis pathway were initially identified through studies of apoptosis in C. elegans (Apaf-1-like proteins, caspases). C. elegans development is highly reproducible and in every developing nematode worm, the same 131 cells die through apoptosis. Two of these cells are the left and right NSM sister cell (NSMsc), and my group has studied the deaths of these two cells for almost 20 years. Importantly, we have now identified mutations that allow us to either increase or decrease the size of the NSMsc. Using these mutations, we have identified an inverse correlation between cell size and the ability of the NSMsc to die. This supports the view that the physical size of a cell can trigger apoptosis in vivo. In the proposed project, we will test this hypothesis. In addition, we will determine which component(s) of the apoptosis pathway are controlled by cell size and how cell size is 'communicated' to this component.The NSMsc are generated through an 'unequal' cell division of a mother cell and are the smaller of the two daughter cells generated. During our studies, we have made the surprising discovery that the apoptosis pathway has a non-canonical function in the control of the size of the NSMsc. Specifically, the apoptosis pathway acts in the mother of the NSMsc and contributes to its unequal division. This ensures that the size of the NSMsc acquires a critical 'lethal size' threshold. In addition, we have evidence that in this context, the caspase directly interacts with a factor that controls the actomyosin cytoskeletal network, which is known to play a critical role during unequal cell divisions. The goal of Aim 2 is to investigate the mechanism(s) through which the caspase affects the actomyosin network during division of the mother of the NSMsc cell, thereby controlling NSMsc size.