Basic Sciences Division, Fred Hutch
Human Biology Division, Fred Hutch
Dr. Emily Hatch studies the nuclear envelope — the membrane that encases the nucleus of the cell — and how changes to its structure can lead to genetic diseases and drive cancer development. Under some conditions, the nuclear envelope can rupture, causing proteins, DNA and even cellular subcompartments to end up in the wrong area of the cell before the envelope either repairs itself or collapses. Dr. Hatch and her team study this process, which has been linked to cancer development and progression. A deeper understanding of this phenomenon may lead to a better understanding of how cancer develops.
Stanford University, 2011, Ph.D. (Biology)
Williams College, 2003, B.A.
Our lab studies the organization and dynamics of the nuclear envelope to understand how changes in this structure cause human genetic diseases and drive cancer development. Our current focus is the mechanisms and consequences of a recently described dynamic where the nuclear membrane ruptures, causing mislocalization of proteins and even organelles, and then either repairs or collapses. This phenomenon has been associated with increased genome instability, inflammation, and metastasis, suggesting that it could be a critical driver of cancer development.
1) What controls nuclear membrane rupture and repair in interphase?
Our current model of NE rupture is that disorganization of the nuclear lamina leads to areas of weak membrane that are prone to both chromatin herniation and membrane rupture when force is applied to the nucleus. The major questions from our model are a) where do large lesions in the nuclear lamina come from, and b) what determines when the membrane ruptures. In addition, there are still many unknowns about how the NE repairs after membrane rupture. Thus, a major project in the lab is to identify the factors that determine nuclear lamina structure and nuclear membrane stability.
2) Why is the nuclear membrane around micronuclei so unstable?
Our previous work showed that defects in the nuclear lamina are apparent in micronuclei soon after mitosis, but that the forces that drive membrane disruption in primary nuclei are not acting on micronuclei. Thus, another aim of the lab is to understand what causes altered nuclear lamina assembly or maintenance in micronuclei and the reason for membrane disruption. Our goal is to both improve our understanding of nuclear envelope assembly in general and to identify new ways to prevent nuclear membrane rupture and lamina defects in cancer cells.
3) What are the consequences of losing nucleus compartmentalization and how does this contribute to human disease?
Although several consequences of persistent nuclear membrane rupture have been identified in micronuclei, it is likely that we have not yet found all the problems caused by this process in either micronuclei or the main nucleus. Thus, we are developing new tools to identify changes in chromatin structure and function, and cellular pathways after nuclear membrane instability. The overall goal of this work is to define causal links between nuclear membrane rupture, misregulation of cellular functions, and disease phenotypes.
1. Hatch, E. M. Nuclear envelope rupture: little holes, big openings. Curr Opin Cell Biol 52, 66–72 (2018).
2. Hatch, E. M. & Hetzer, M. W. Nuclear envelope rupture is induced by actin-based nucleus confinement. J. Cell Biol. 114, jcb.201603053–36 (2016).
3. Hatch, E. M., Fischer, A. H., Deerinck, T. J. & Hetzer, M. W. Catastrophic nuclear envelope collapse in cancer cell micronuclei. Cell 154, 47–60 (2013).
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