Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients.
Proceedings of the National Academy of Sciences of the United States of America
washington; seattle; isb
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 the detection of CTCs. In 59 NSCLC patients bearing cytokeratin-positive (CKpos) primary tumors, HK2 enables resolving cytokeratin-negative (HK2high/CKneg) CTCs as a prevalent population in about half of the peripheral blood samples with positive CTC counts. However, HK2high/CKneg tumor cells are a minority population in pleural effusions and cerebrospinal fluids. Single-cell analysis shows that HK2high/CKneg CTCs exhibit smaller sizes but consistent copy number variation profiles compared with CKpos counterparts. Single-cell transcriptome profiling reveals that CK expression levels of CTCs are independent of their epithelial-to-mesenchymal transition (EMT) status, challenging the long-standing association between CK expression and EMT. HK2high/CKneg CTCs display metastasis and EGFR inhibitor resistance-related molecular signatures and are selectively enriched in patients with EGFR L858R driver oncogene mutation as opposed to EGFR 19Del , which is more frequently found in patients with prevalent CKpos CTCs in the blood. Consistently, treatment-naïve patients with a larger number or proportion of HK2high/CKneg CTCs in the blood exhibit poor therapy response and shorter progression-free survival. Collectively, our approach resolves a more complete spectrum of CTCs in NSCLC that can potentially be exploited to identify patient prognosis before therapy.
Institute for Systems Biology
Yang, Liu; Yan, Xiaowei; Chen, Jie; Zhan, Qiong; Hua, Yingqi; Xu, Shili; Li, Ziming; Wang, Zhuo; Dong, Yu; Zuo, Dongqing; Xue, Min; Tang, Yin; Herschman, Harvey R; Lu, Shun; Shi, Qihui; and Wei, Wei, "Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients." (2021). Articles, Abstracts, and Reports. 4758.