A recent study led by a team from New York University advances our understanding of the function of mechanical constraints in glioblastoma (GBM), the most aggressive type of brain tumor. The researchers explored the underlying mechanotransductive machinery involved in the mechanical constraints-mediated emergence and spatial patterning of cancer stem cells (CSCs) in GBM.
Using a 2D micropatterned multicellular model, the researchers revealed that Piezo1, a mechanosensitive channel, collaborates with focal adhesions, cadherins, and the downstream cytoskeletal machinery to regulate the mechanosensing of cancer cells to mechanical constraints in the GBM tumor microenvironment. This, in turn, guides the spatial patterning of CSCs within the tumor.
GBM is characterized by a high fraction of CSCs, a subpopulation of cancer cells with self-renewal and tumor-initiating capacities. These CSCs are tightly associated with tumorigenesis, metastasis, treatment resistance, and poor patient survival. However, the origin of CSCs in GBM is not fully understood, with both intrinsic and extrinsic factors playing a role.
One of the major mechanical characteristics of GBM is the accumulated stress inside the tumor due to the physical confinement of the rigid skull. This mechanical constraint impacts both the cell body and nucleus, leading to cellular alterations such as deformability, traction force, and changes in gene transcription. Importantly, the gradients of mechanical stresses generated within the confined tumor microenvironment can mechanically induce a malignant phenotype in cancer cells and influence the emergence and spatial distribution of CSCs.
The study, published in Mechanobiology in Medicine, found that in different geometric multicellular patterns, GBM cells in the peripheral regions expressed higher levels of CSC markers, corresponding to the gradients of mechanical stresses generated within the confined environment. The researchers further demonstrated that the upregulation of Piezo1 plays a critical role in the phenotypic switch of GBM cells to CSCs, highlighting the importance of the interplay between cell-ECM and cell-cell interactions in regulating the emergence and spatial patterning of CSCs in GBM.
These findings underscore the pivotal role of mechanical forces originating from cellular contractility and intercellular interactions, which emerge from the mechanical constraints in the multicellular organization, in determining the unique spatial patterns of CSCs in GBM. This study provides valuable insights into the mechanistic underpinnings of GBM progression and may inform the development of targeted therapies.