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Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation.

Wen Yih AwCrescentia ChoHao WangAnne Hope CooperElizabeth L DohertyDavid J RoccoStephanie A HuangSarah KubikChloe P WhitworthRyan ArmstrongAnthony J HickeyBoyce E GriffithMatthew L KutysJulie BlattWilliam J Polacheck
Published in: Science advances (2023)
Somatic activating mutations of PIK3CA are associated with development of vascular malformations (VMs). Here, we describe a microfluidic model of PIK3CA -driven VMs consisting of human umbilical vein endothelial cells expressing PIK3CA activating mutations embedded in three-dimensional hydrogels. We observed enlarged, irregular vessel phenotypes and the formation of cyst-like structures consistent with clinical signatures and not previously observed in cell culture models. Pathologic morphologies occurred concomitant with up-regulation of Rac1/p21-activated kinase (PAK), mitogen-activated protein kinase cascades (MEK/ERK), and mammalian target of rapamycin (mTORC1/2) signaling networks. We observed differential effects between alpelisib, a PIK3CA inhibitor, and rapamycin, an mTORC1 inhibitor, in mitigating matrix degradation and network topology. While both were effective in preventing vessel enlargement, rapamycin failed to reduce MEK/ERK and mTORC2 activity and resulted in hyperbranching, while inhibiting PAK, MEK1/2, and mTORC1/2 mitigates abnormal growth and vascular dilation. Collectively, these findings demonstrate an in vitro platform for VMs and establish a role of dysregulated Rac1/PAK and mTORC1/2 signaling in PIK3CA -driven VMs.
Keyphrases
  • signaling pathway
  • protein kinase
  • pi k akt
  • endothelial cells
  • high throughput
  • gene expression
  • high resolution
  • cell migration
  • genome wide
  • radiation therapy
  • locally advanced
  • hyaluronic acid