Joining Soon: Yekaterina (Kate) Miroshnikova, Ph.D., Stadtman Tenure-Track Investigator
Dr. Miroshnikova and the Section on Nuclear Mechanotransduction and Cell Fate Dynamics are joining the Laboratory of Molecular Biology in July 2021.
Postdoctoral fellows, graduate students, and post-baccalaureate available.
- EMBO/HFSP Postdoctoral Fellow, Max Planck Institute for Biology of Ageing, Cologne Germany and Helsinki Institute of Life Sciences, Helsinki Finland 2016-2020
- Whitaker Postdoctoral Fellow, Institute for Advanced Biosciences, Grenoble France, 2015-2017
- Ph.D. Bioengineering, University of California San Francisco and Berkeley, USA, 2015
- B.S. Engineering Franklin W. Olin College of Engineering, USA, 2009
We study how cells sense and integrate mechanical and chemical information from their environment to control cell state and behavior. We are particularly interested how the nucleus responds to these mechanochemical signals to alter chromatin architecture and gene expression. Our interdisciplinary research combines scale-bridging tools ranging from tissue-level live imaging, mechanical manipulation, and various genomics approaches to nanoscale atomic force microscopy to understand fundamental principles of cell and tissue maintenance and how this regulation becomes perturbed in cancer.
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.
Applying our Research
Decades of research have established clear correlations between tissue mechanics and cancer aggression. Strikingly, however, no mechanical measurement or biomarker has reached the clinics as a routinely used molecular diagnostic tool. One major reason for this is that these measurements are technically challenging and labor-intensive. Thus, there is a substantial clinical need to develop mechanobiological markers based on morphometry, immunohistochemistry or emerging sequencing-based methods. By discovering fundamental differences between the mechanical regulation of normal and cancer cells, our research aims to improve cancer diagnostics and targeted cancer therapies.
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.
- Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage
- Nava MM and Miroshnikova Y.A., Biggs LC, Whitefield DB, Vihinen H, Jokitalo E, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Noel Dahl K, and Wickström S.A Cell 2020 May 14;181(4):800-817 Abstract/Full Text
- Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification
- Miroshnikova YA, Le HQ, Schneider D, Thalheim T, Rübsam M, Bremicker N, Polleux J, Kampard N, Tarantola M, Wang I, Balland M, Niessen CM, Galle J, Wickström SA Nat Cell Biol 2018 Jan;20(1):69-80 Abstract/Full Text
- Emerging roles of mechanical forces in chromatin regulation
- Miroshnikova YA, Nava MM, and Wickström SA Cell Sci 2017 130(14):2243-2250 Abstract/Full Text
- Tissue mechanics promote IDH1-dependent Hif1α-Tenascin C feedback to regulate glioblastoma aggression
- Miroshnikova YA, Mouw JK, Barnes JM, Pickup MW, Lakins JN, Kim Y, Lobo K, Persson AI, Reis GF, McKing TR, Holland EC, Phillips JJ, and Weaver, WM Nat Cell Biol 2016;18(12):1336-1345 Abstract/Full Text
- Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression
- Laklai, H., Miroshnikova YA, Pickup MW, Collison EA, Kim G, Barret AS, Hill RC, Lakins JN, Schlaepfer DD, Mouw JK, et al. and Weaver, WM Nat Med 2016 22(5):497-505 Abstract/Full Text