Urinary detection of lung cancer in mice via noninvasive pulmonary protease profiling.
Jesse D KirkpatrickAndrew D WarrenAva P SoleimanyPeter M K WestcottJustin C VoogCarmen Martin-AlonsoSangeeta N BhatiaTuomas TammelaTyler JacksSangeeta N BhatiaPublished in: Science translational medicine (2021)
Lung cancer is the leading cause of cancer-related death, and patients most commonly present with incurable advanced-stage disease. U.S. national guidelines recommend screening for high-risk patients with low-dose computed tomography, but this approach has limitations including high false-positive rates. Activity-based nanosensors can detect dysregulated proteases in vivo and release a reporter to provide a urinary readout of disease activity. Here, we demonstrate the translational potential of activity-based nanosensors for lung cancer by coupling nanosensor multiplexing with intrapulmonary delivery and machine learning to detect localized disease in two immunocompetent genetically engineered mouse models. The design of our multiplexed panel of sensors was informed by comparative transcriptomic analysis of human and mouse lung adenocarcinoma datasets and in vitro cleavage assays with recombinant candidate proteases. Intrapulmonary administration of the nanosensors to a Kras- and Trp53-mutant lung adenocarcinoma mouse model confirmed the role of metalloproteases in lung cancer and enabled accurate detection of localized disease, with 100% specificity and 81% sensitivity. Furthermore, this approach generalized to an alternative autochthonous model of lung adenocarcinoma, where it detected cancer with 100% specificity and 95% sensitivity and was not confounded by lipopolysaccharide-driven lung inflammation. These results encourage the clinical development of activity-based nanosensors for the detection of lung cancer.
Keyphrases
- mouse model
- disease activity
- low dose
- computed tomography
- machine learning
- rheumatoid arthritis
- systemic lupus erythematosus
- loop mediated isothermal amplification
- single cell
- inflammatory response
- real time pcr
- label free
- newly diagnosed
- ejection fraction
- metabolic syndrome
- squamous cell carcinoma
- magnetic resonance
- wild type
- immune response
- big data
- toll like receptor
- deep learning
- high dose
- positron emission tomography
- young adults
- juvenile idiopathic arthritis
- crispr cas
- artificial intelligence
- skeletal muscle
- climate change
- risk assessment
- room temperature
- quality improvement
- high fat diet induced
- patient reported outcomes
- peritoneal dialysis
- low cost
- squamous cell
- image quality
- pet ct
- dual energy