@article{aw_cho_wang_cooper_doherty_rocco_huang_kubik_whitworth_armstrong_et al._2023, title={Microphysiological model of PIK3CA-driven vascular malformations reveals a role of dysregulated Rac1 and mTORC1/2 in lesion formation}, volume={9}, ISSN={["2375-2548"]}, DOI={10.1126/sciadv.ade8939}, abstractNote={
            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.
          }, number={7}, journal={SCIENCE ADVANCES}, author={Aw, Wen Yih and Cho, Crescentia and Wang, Hao and Cooper, Anne Hope and Doherty, Elizabeth L. and Rocco, David and Huang, Stephanie A. and Kubik, Sarah and Whitworth, Chloe P. and Armstrong, Ryan and et al.}, year={2023}, month={Feb} }