Mechanosensitive brain tumor cells construct blood-tumor barrier to mask chemosensitivity

Neuron. 2023 Jan 4;111(1):30-48.e14. doi: 10.1016/j.neuron.2022.10.007. Epub 2022 Nov 1.


Major obstacles in brain cancer treatment include the blood-tumor barrier (BTB), which limits the access of most therapeutic agents, and quiescent tumor cells, which resist conventional chemotherapy. Here, we show that Sox2+ tumor cells project cellular processes to ensheathe capillaries in mouse medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-catenin. Piezo2 knockout reverses WNT/β-catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances the MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie treatment failures in brain cancer.

Keywords: Piezo2; WNT/β-catenin signaling; blood-tumor barrier; brain tumor; chemosensitivity; mechanosensitive ion channel; medulloblastoma; quiescence; tissue mechanics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism
  • Brain / metabolism
  • Brain Neoplasms* / drug therapy
  • Brain Neoplasms* / pathology
  • Endothelial Cells / metabolism
  • Ion Channels / metabolism
  • Mice
  • beta Catenin* / metabolism
  • beta Catenin* / therapeutic use


  • beta Catenin
  • Ion Channels