Abstract 777: Super-resolution imaging of heterochromatin structure detects early events in lung cancer
Authors: Stabile Laura P. , Sun Xuejiao , Xu Jianquan , Kanterewicz Beatriz , Wilson David O. , Dacic Sanja , Rigatti Lora H. , Diergaarde Brenda , Liu Yang 
Published: April 2023

Abstract
Early detection of lung cancer is essential to reduce lung cancer-related morbidity and mortality. Despite significant efforts, current approaches suffer from high false-positive rates or limited sensitivity. There is a critical need for non-invasive, cost-effective technologies that detect the early changes in lung carcinogenesis with high sensitivity and specificity. Abnormal chromatin structure is one of the hallmarks of cancer cells and is independent of molecular pathways making it an attractive target for early cancer detection. In this study, we assessed the use of super-resolution stochastic optical reconstruction microscopy (STORM) to detect abnormal heterochromatin disruption in lung carcinogenesis. First, utilizing a mouse model of tobacco carcinogen (NNK)-induced lung adenocarcinoma, we analyzed heterochromatin structure in the lungs of NNK-treated mice at 8, 15 and 20 weeks post-NNK exposure together with non-treated control mice at the same time points. Super-resolution images of NNK-induced lung lesions at all time points showed significant disruption of condensed heterochromatin nanodomains compared to normal alveolar epithelial cells from the control mice, consistent with our data from other tumor types. Importantly, the normal-appearing bronchial epithelial cell nuclei from NNK-treated mice also showed significant heterochromatin disruption in NNK-treated mice at 15 and 20 weeks (P&lt; 0.0001), demonstrating that this method can detect early changes. Next, we sought to confirm this in humans. Super-resolution imaging showed that, compared to normal alveolar and bronchial epithelial cells from control subjects without cancer, the heterochromatin structure was more disrupted in tumor cells from patients with lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). We also observed significant disrupted heterochromatin structure in tumor-adjacent normal tissue at the tumor margin. Lastly, we performed a pilot study on bronchial epithelial cells isolated from sputum samples from 11 cigarette smokers with or without lung cancer. The heterochromatin structure in the bronchial epithelial cells collected from lung cancer patients at the time of diagnosis was significantly more disrupted than those from smokers without lung cancer (P= 0.004). Our results support disrupted heterochromatin structure as an early event in lung carcinogenesis and demonstrate the feasibility of utilizing super-resolution imaging of heterochromatin structure for early detection of lung cancer using sputum samples.
Citation Format: Laura P. Stabile, Xuejiao Sun, Jianquan Xu, Beatriz Kanterewicz, David O. Wilson, Sanja Dacic, Lora H. Rigatti, Brenda Diergaarde, Yang Liu. Super-resolution imaging of heterochromatin structure detects early events in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 777.