Profile
The Wickström lab combines state-of-the-art scale-bridging technologies from nanoscale atomic force microscopy and next-generation sequencing to novel ex vivo tissue culture methods, the whole organism live imaging and in silico modeling all the way up to analysis of the clinical patient material. The research is highly interdisciplinary and involves collaborations with mathematicians, physicists, and clinical oncologists. Recent work from the Wickström group has uncovered how a generation of cellular forces is important for controlling stem cell fate and coordinating cell fate with cell position within the tissue. Furthermore, the laboratory has discovered how extrinsic forces generated by the tissue impact chromatin structure and epigenetic gene silencing, thereby controlling the transcriptional state and lineage commitment of stem cells. Read more about the ongoing projects below.
Recent Research Highlights
1. Discovery of a novel mechanisms by which mechanical force regulates nuclear architecture and chromatin structure, thereby impacting genome stability and stem cell fate
Mammalian cells are continuously exposed to mechanical signals emanating from their dynamic microenvironment and that influence key developmental and homeostatic processes. Important examples include the critical role of shear stress generated by flow in the development and homeostasis of the cardiovascular system, and the role of strain generated by tissue stretch in controlling growth of epithelial tissues. While the link between mechanical forces and cell behavior is well-established and has been a subject of intense investigations, the mechanisms by which forces control genome activity to direct cell state dynamics have remained undefined. We discovered that mechanical forces prevent adult stem lineage commitment by inducing global chromatin silencing in epidermal stem cells. In a parallel study, we uncovered how force induces calcium-dependent nuclear softening driven by loss heterochromatin proximal to the nuclear lamina. The resulting changes in chromatin mobility, viscoelasticity, and architecture are required to insulate genetic material from mechanical force. Failure to mount this nuclear mechanoresponse results in DNA damage. Both of these force-dependent chromatin changes are regulated by nuclear deformation, identifying the nucleus as an independent mechanosensor in cells. In our most recent study extending these observations, we identified the molecular mechanism underlying force-induced chromatin remodeling and explained the kinetics of these responses. We found that nuclear deformation generates an osmotic stress-like state driven by increased macromolecular crowding within the nuclear interior. This mechano-osmotic signaling cascade triggers rapid chromatin compaction while simultaneously remodeling nuclear condensates harboring key epigenetic regulators, resulting in rapid enhancer restructuring at critical differentiation loci. Our results thus reveal how mechanical signals integrate nuclear architecture, chromatin organization and transcriptional regulation to control lineage commitment and facilitate mechanoadaptation.
- Le HQ, Ghatak S, Yeung CC, Tellkamp F, Günschmann C, Dieterich C, Yeroslaviz A, Habermann B, Pombo A, Niessen CM, Wickström SA (2016) Mechanical regulation of transcription drives Polycomb-mediated gene silencing during lineage commitment. Nat Cell Biol 18, 864-875.
- Nava MM, Miroshnikova YA, Biggs LC, Whitefield DB, Metge F, Boucas J, Vihinen H, Jokitalo E, Li X, García Arcos JM, Hoffmann B, Merkel R, Niessen CM, Dahl KN, Wickström SA. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage Cell 181, 800-817
- McCreery KP, Stubb A, Stephens R, Fursova NA, Cook A, Kruse K, Michelbach A, Biggs LC, Keikhosravi A, Nykänen S, Hydén-Granskog C, Zou J, Lackmann JW, Niessen CM, Vuoristo A, Miroshnikova YA, Wickström SA (2025) Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells. Nat Cell Biol; 27(10):1757-1770.
2. Deciphering fundamental mechanisms of epithelial morphogenesis and disease
To regulate organ size and function, self-renewing tissues must balance stem cell proliferation and differentiation rates to scale with organism size while coordinating cell fate with spatial position. We have employed stratified epithelial development and cancer as experimental paradigms, utilizing both human clinical specimens and mouse models, to elucidate the principles governing this coordination. Using murine epidermis as a model system, we identified the mechanism enabling the observed balance between self-renewal and differentiation during development. Through quantitative measurement of tissue stresses and tension, we discovered that this balance is coordinated by local mechanical forces generated by cell division and delamination. Proliferation within the stem cell layer, which exhibits characteristics of a solid-like material, mechanically distorts neighboring cells. The resulting alterations in cortical tension and cell-cell adhesion control differentiation, thereby restoring basal layer cell density. Similar tissue scale mechanical changes control formation of hair follicles in the same tissue. These results reveal the self-organizing principles governing epithelial organ growth and differentiation.
We applied this mechanistic understanding of tissue dynamics to develop a machine learning-based platform for quantifying tissue architecture and cell states in human oral squamous cell carcinoma, identifying a composite morphomolecular biomarker with high prognostic value for patient survival. We further elucidated the mechanistic basis for this prognostic association, discovering pro-invasive reprogramming of cancer cells by stromal signals at the tumor-stroma interface.
- Punovuori K, Bertillot F, Miroshnikova YA, Binner MI, Myllymäki SM, Follain G, Kruse K, Routila J, Huusko T, Pellinen T, Hagström J, Kedei N, Ventelä S, Mäkitie A, Ivaska J, Wickström SA. Multiparameter imaging reveals clinically relevant cancer cell-stroma interaction dynamics in head and neck cancer (2024) Cell 187(25):7267-7284.
- Villeneuve C, Hashmi A, Ylivinkka , Lawson-Keister E, Miroshnikova YA, Perez-Gonzalez C, Yadav B, Zhang T, Matic Vignevic D, Mikkola ML, Mannin ML, Wickström SA. Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture. Nat Cell Biol 26 (2), 207-218
- Bansaccal N, Vieugue P, Sarate R, Song Y, Minguijon E, Miroshnikova YA, Zeuschner D, Collin A, Allard J, Engelman D, Delaunois AL, Liagre M, de Groote L, Timmerman E, Van Haver D, Impens F, Salmon I, Wickström SA, Sifrim A, Blanpain C (2023) The extracellular matrix dictates regional competence for tumour initiation. Nature 623(7988):828-835
- Miroshnikova YA, Le, HQ, Schneider D, Thalheim T, Rübsam M, Bremicker N, Polleux J, Höppner N, Tarantola M, Wang I, Balland M, Niessen CM, Galle J, Wickström SA (2018) A biomechanical network of adhesion forces and cell mechanics couples proliferation and differentiation to drive epidermal stratification. Nat Cell Biol 20:69-80