Mechanobiology in health and disease
Cells in tissues are constantly sensing their extracellular environment and responding to physical cues by activating specific mechanosignaling routes that control cellular fate. Alterations in the biophysical environment can lead to rapid reorganization of the cytoskeletal structures, and later to changes in gene expression levels. This kind of an ability of the cells to sense and respond to their biophysical environment is crucial in maintaining both the integrity and specific functions of the tissues.
Integrity of the epithelial tissues is maintained by cytoskeletal structures that together with cell-adhesive complexes form a tissue-supporting network. Of these cytoskeletal structures, actomyosin bundles, provide force for the integration of the epithelia. Generation of cell-exerted actomyosin forces are largely determined by the physical cues from the extracellular matrix and any abnormalities in the biophysical stroma may compromise tissue integrity through disturbance of the normal cellular force production. Mechanical changes of the stroma are thus associated with a number of pathological conditions via deregulation of the cytoskeletal structures as well as altered gene expression. Abnormal tissue mechanics is for instance linked to invasive carcinomas, cardiovascular diseases, airway diseases and fibrosis.
In our studies we aim in understanding how epithelial, force-producing actomyosin structures maintain the integrity of mammary epithelia. How is the dynamics of actomyosin bundles controlled by specific physical properties of the extracellular environment and how is their regulation compromised upon scattering of cancer cells? Cancer invasion and subsequent formation of distant metastasis is clearly a major clinical issue and the role of stroma in the neoplastic progression is still poorly understood. In our research we focus on mammary tissue but the mechanism behind the maintenance of other epithelial sheets are expected be similar.
Model systems and methodology
In our studies we utilize both human and canine mammary epithelial cells, and a variety of molecular- and cell biological methods, proteomics, histo-pathological methods as well as advanced imaging methods. In addition to established cell lines and primary cells from tissue bank, we utilize patient samples isolated from either normal or transformed canine mammary glands in 3D organoid cultures and as live tissue slices.
Why do we use canine as a comparative model ?
Dogs are known to act as an excellent model for several human diseases. Spontaneous diseases, developed in dogs, often share the genetic background and the same risk factors for the onset as corresponding human diseases. Canine mammary tumors (CMTs) for instance provide an excellent natural model for the heterogeneous group of human breast carcinomas. Compared to human, CMTs have histopathologically similar cancer subtypes as well as pre-neoplasias and share the same risk factors for the onset of this disease. Additionally, the expression of several lineage-specific markers in basal and luminal cell populations is identical in canine and human. Canine mammary material is received from the patients of Helsinki University Small Animal Hospital after tumor removal. This patient material is undergoing histopathological examination and specific cell types are also isolated for further studies in cell culture to understand the interplay in between epithelia and stroma.
In the Image: Examples on utilized methodology. In our studies we utilize a wide variety of different methods from histopathological screening to advanced 3D culture setups and more biophysical methods. Casts for 3D space-and stiffness-determined scaffolds have been provided by the group of S. Franssila, Aalto University.