Cancer remains a leading cause of death worldwide. In the US, there are over 1.5 million new diagnoses and half million deaths annually. Over 90% of solid tumors (e.g., breast, colorectal) are characterized by chromosomal abnormalities including aneuploidy, the loss or gain of chromosomes, which contributes to the genomic instability that drives cancer development. Aneuploidy arises from defects in chromosome segregation during mitosis. In late mitosis, the intercellular bridge (ICB) that connects the two compartments of a dividing cell is severed by a process termed abscission. Abscission provides a mechanism for delaying cell division in the presence of missegregated chromosomes (NoCut checkpoint) that are trapped in the ICB. Thus, defects in abscission and the NoCut checkpoint result in aneuploidy and chromosome damage. Abscission involves the constriction and severing of the ICB membrane by the endocytic sorting complex required for transport-III (ESCRT-III). Assembly of this multi-component membrane complex is spatially and temporally regulated, and requires the targeting and fusion of ESCRT-III-carrying endosomes with the ICB. To date, however, very little is known about of how ESCRT-III assembly is spatio-temporally coordinated with endosome fusion and how it is linked to the NoCut checkpoint. Septins are GTP-binding proteins that are abnormally expressed in many cancers. Septins assemble into higher order structures that control the spatial organization of membrane and cytosolic proteins. In yeast, septins are essential for the spatial coordination of cytokinesis. In mammalian cells, septins are required for the completion of abscission, but their functions are poorly understood. Based on preliminary data, we hypothesize that septins regulate the assembly of the ESCRT-III complex. Here, we will determine how septins function in the recruitment and assembly of ESCRT- III subunits into rings and spiral filaments. We will test for septin roles in the spatial organization of the ESCRT- III complex and the endosomal delivery of its components. Importantly, the proposed work will examine how abnormalities in septin expression, which are common in cancer, affect the NoCut checkpoint. The proposed studies require training in cutting edge methods of light and electron microscopy (EM) including structured illumination super-resolution microscopy and correlative light and platinum replica EM. The overarching goal of this pre-doctoral fellowship project is to prepare for an independent career in the broader areas of cell and cancer biology. In summary, the proposed project will shed new insights into the mechanisms of cytokinetic abscission and septins, which are abnormally expressed in many cancers, but their roles remain poorly understood.
In spite of recent medical advances, cancer remains a leading cause of death world wide with over 1.5 million new diagnoses and 0.5 million deaths each year in the US alone. Hallmarks of cancer are abnormal chromosome gains or losses, which occur when critical checkpoints of cell division fail, promoting the development of cancer. This research aims to understand how septins, a group of proteins whose expression is missregulated in many cancers, function in the last step and checkpoint of cell division, and therefore will shed new insights into the cause of cancer and how septins can be targeted for cancer therapies.
|Karasmanis, Eva P; Phan, Cat-Thi; Angelis, Dimitrios et al. (2018) Polarity of Neuronal Membrane Traffic Requires Sorting of Kinesin Motor Cargo during Entry into Dendrites by a Microtubule-Associated Septin. Dev Cell 46:204-218.e7|