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Rationally Designed 3D Hydrogels Model Invasive Lung Diseases Enabling High‐Content Drug Screening
Author(s) -
Tam Roger Y.,
YockellLelièvre Julien,
Smith Laura J.,
Julian Lisa M.,
Baker Alexander E. G.,
Choey Chandarong,
Hasim Mohamed S.,
Dimitroulakos Jim,
Stanford William L.,
Shoichet Molly S.
Publication year - 2019
Publication title -
advanced materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.707
H-Index - 527
eISSN - 1521-4095
pISSN - 0935-9648
DOI - 10.1002/adma.201806214
Subject(s) - lymphangioleiomyomatosis , mtorc1 , self healing hydrogels , cancer research , drug , lung , biology , cell , tuberous sclerosis , materials science , microbiology and biotechnology , signal transduction , pathology , pharmacology , medicine , pi3k/akt/mtor pathway , biochemistry , polymer chemistry
Cell behavior is highly dependent upon microenvironment. Thus, to identify drugs targeting metastatic cancer, screens need to be performed in tissue mimetic substrates that allow cell invasion and matrix remodeling. A novel biomimetic 3D hydrogel platform that enables quantitative analysis of cell invasion and viability at the individual cell level is developed using automated data acquisition methods with an invasive lung disease (lymphangioleiomyomatosis, LAM) characterized by hyperactive mammalian target of rapamycin complex 1 (mTORC1) signaling as a model. To test the lung‐mimetic hydrogel platform, a kinase inhibitor screen is performed using tuberous sclerosis complex 2 (TSC2) hypomorphic cells, identifying Cdk2 inhibition as a putative LAM therapeutic. The 3D hydrogels mimic the native niche, enable multiple modes of invasion, and delineate phenotypic differences between healthy and diseased cells, all of which are critical to effective drug screens of highly invasive diseases including lung cancer.