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Resolving an underrepresented circulating tumor cell population in lung cancer enabled by Hexokinase 2 analysis

By Liu Yang, Xiaowei Yan, Jie Chen, Qiong Zhan, Yingqi Hua, Shili Xu, Yu Dong, Ziming Li, Zhuo Wang, Dongqing Zuo, Min Xue, Yin Tang, Harvey R Herschman, Shun Lu, Qihui Shi, Wei Wei

Posted 29 Apr 2020
bioRxiv DOI: 10.1101/2020.04.27.064345

Unlike other epithelial cancer types, circulating tumor cells (CTCs) are less frequently detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients using epithelial marker-based detection approaches, despite the aggressive nature of NSCLC. Here we demonstrate hexokinase-2 (HK2) as a metabolic function-associated marker for detection of CTCs, with significantly improved detection rates and high specificity, in 33 NSCLC patients. Use of the HK2 marker identified underrepresented cytokeratin-negative (HK2high/CKneg) CTCs present in many blood samples but rarely detected in pleural effusions or cerebrospinal fluids of NSCLC patients. HK2high/CKneg CTCs exhibited smaller sizes but consistent copy number variation profiles compared to CKpos CTCs. Surprisingly, CK expression levels were found to be independent of CTC epithelial-to-mesenchymal transition (EMT) status as measured by single-cell transcriptome profiling, challenging the long-standing association between CK expression and EMT. Our approach improves sensitivity of CTC detection in NSCLC and can potentially resolve a more complete spectrum of CTCs, regardless of their CK expression levels or epithelial traits. ### Competing Interest Statement The authors have declared no competing interest.

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