Yekaterina (Kate) Miroshnikova, Ph.D., Stadtman Tenure-Track Investigator

Research Goal

Using cutting-edge, interdisciplinary approaches Miroshnikova lab aims to understand the role of nuclear mechanotransduction in modulating genome architecture and gene expression patterns to tune stem cell fate.

Current Research

Cells within active, self-renewing tissues such as the intestine and skin epidermis are constantly exposed to cell- and tissue-level forces that result in changes in nuclear shape and volume. Given the critical role of the three-dimensional organization of chromatin in transcriptional regulation, it is of importance to understand how nuclear shape and volume changes that occur during processes such as cell motility, polarization, and differentiation trigger specific changes in gene expression. Furthermore, nuclear shape and size abnormalities, in combination with chromatin distribution, are routinely utilized by clinicians to diagnose various cancers, highlighting the importance of detecting irregularities in nuclear shape. Yet, what precisely determines nuclear shape in health and disease, and how this is linked to cell fate and function remains a fundamental open question. Our laboratory addresses these key questions within two main research areas.

Extrinsic mechanical forces and nuclear deformation as active players in stem cell fate specification

It is known that mechanical forces that deform cells and their nuclei can alter chromatin state and transcription (Le et al. Nat. Cell Biol. 2016, Miroshnikova J. Cell Sci. 2017, Tajik et al. Nat. Mater., Nava, Miroshnikova Cell 2020), but the mechanisms remain unclear. Specifically, it is not clear if force-activated gene regulation involves direct, specific movements and remodeling of chromatin. Further is it not clear if force application can lead to permanent, fate-altering cellular events. To answer these questions we utilize induced pluripotent stem cells (iPS) in combination with 2- and 3-dimensional niche engineering, spectrum of mechanical manipulations coupled to high resolution genomics analyses and imaging to decipher both the short term transcriptional and chromatin accessibility effects, as well as long-term consequences on iPS differentiation trajectories.

Nuclear morphology and mechanics as functional and prognostic entities in intestinal homeostasis and colorectal cancer progression

A key open question in the field of epithelial cancers is at what precise stage of cancer do nuclear abnormalities arise and how do they affect cancer progression and aggression. Two hypotheses have emerged with respect to the relationship between nuclear shape, mechanics, and function. The first postulates that changes in nuclear shape and architecture alter bulk nuclear stiffness in order to allow cells to squeeze through tight spaces during invasion (soft nucleus) or withstand high mechanical loading (stiff nucleus) (Dahl et al. Circ. Res. 2008). The second hypothesis proposes that nuclear architecture abnormalities drive further genome instability and thus promote cancer progression (Webster et al J. Cell Sci 2009). These two hypotheses are not mutually exclusive. We investigate both the biophysical and genomic mechanisms and functional consequences of altered nuclear shape during cancer progression using clinical patient samples and patient-derived organoids.

Research in Plain Language

Organs of our body are made up of an ensemble of different, functionally specialized cell types. Most cells contain a nucleus which holds within it genetic information in the form of DNA, which encodes for genes, of which a tightly selected subset needs to be transcribed into mRNA and subsequently protein to generate and maintain these specialized cell states. In everyday life as we move and breathe, and on smaller scales as our organs are dynamically self-renewed or repaired, our cells are compressed, stretched and deformed. Our research aims to understand how cells and tissues cope with deformation and mechanical stress that they are constantly exposed to without being damaged. We further investigate how these mechanical forces act as signals to instruct cell behavior and change cell morphology. Finally, we investigate how these mechanisms get corrupted with cancer.

Tight regulation of the 3-dimensional organization of the genome, its transcriptional output, as well as general safeguarding of genome integrity, is crucial for maintaining cell functionality and thus human health. We focus on understanding how healthy stem cells, which are long-lived cells, manage to maintain the integrity of their DNA and nuclei under a variety of chemical and physical environmental insults and extend this knowledge to understand how these mechanisms get corrupted in cancer stem cells. We further aim to understand how forces alter nuclear shape and thereby potentially also the 3-dimensional organization of the genome and transcription of individual genes. We aim to gain a deep enough mechanistic understanding of this process to uncover how defects in these processes, collectively termed nuclear mechanotransduction, allows cancer formation and evasion of control mechanisms that exist within our tissues. This work will allow us to deepen our understanding of how nuclear integrity is maintained in health, as well as open up new cancer stem cell-specific therapeutic strategies.