Urinary detection of lung cancer in mice via noninvasive pulmonary protease profiling
Menée in vitro et à l'aide de modèles murins d'adénocarcinome pulmonaire, cette étude évalue l'intérêt d'une approche diagnostique consistant à administrer par instillation intratrachéale un substrat qui, clivé par des protéases de la périphérie tumorale, libère un ensemble de molécules détectées dans les urines par chromatographie en phase liquide couplée à la spectrométrie de masse puis analysées à l'aide de l'intelligence artificielle
Previously developed nanoparticle technology has been shown to detect the hallmark protease activity of many cancers, amplifying it into a urinary readout. Now, Kirkpatrick et al. optimize protease activity–based nanosensors for the detection of lung cancer. Intratracheal instillation of nanosensors enabled detection of localized lung adenocarcinoma in two immunocompetent, autochthonous mouse models. The sensors distinguished between lung cancer and lung inflammation, and did not detect protease activity in a colorectal cancer xenograft model. Further work will need to confirm the approach for human lung cancer and other lung cancer subtypes and to formulate the nanosensors for intrapulmonary delivery in patients.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.
Science Translational Medicine , résumé, 2019