Rationally Designed 3D Hydrogels Model Invasive Lung Diseases Enabling High-Content Drug Screening.
Roger Y TamJulien Yockell-LelièvreLaura J SmithLisa M JulianAlexander E G BakerChandarong ChoeyMohamed S HasimJim DimitroulakosWilliam L StanfordMolly S ShoichetPublished in: Advanced materials (Deerfield Beach, Fla.) (2018)
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.
Keyphrases
- high throughput
- drug delivery
- induced apoptosis
- single cell
- tissue engineering
- hyaluronic acid
- cell cycle arrest
- wound healing
- genome wide
- small cell lung cancer
- cell therapy
- squamous cell carcinoma
- cancer therapy
- machine learning
- stem cells
- drug release
- endoplasmic reticulum stress
- extracellular matrix
- deep learning
- dna methylation
- signaling pathway
- high resolution
- emergency department
- cell migration
- big data
- cell cycle
- drug induced
- young adults