Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients
Menée à partir d'échantillons sanguins et d'échantillons d'épanchements pleuraux prélevés sur des patients atteints d'un cancer du poumon non à petites cellules de stade III ou IV, cette étude met en évidence une association entre un niveau élevé de cellules tumorales circulantes exprimant fortement l'hexokinase 2 et un pronostic défavorable
This work demonstrates that HK2-based assay can resolve a novel HK2high/CKneg CTC population with consistent genomic CNV but distinct transcriptome signatures compared to the CKpos counterpart in NSCLC patients. CK expression levels are found independent of cellular EMT status in these CTCs and may be related to distinct dissemination mechanisms in different types of body fluids. Selective association of CK subtypes in CTCs with patient EGFR mutation types may contribute to suboptimal EGFR inhibitor therapeutic efficacy in EGFRL858R mutant tumors, enabling prediction of patients with poor prognosis before therapy. More generally, HK2, as a metabolic function–associated marker, is likely to be useful in identifying CTCs from patients with a wide variety of cancers, independent of epithelial traits.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 EGFRL858R driver oncogene mutation as opposed to EGFR19Del, 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.The single-cell sequencing data reported in this paper have been deposited in the ArrayExpress database (accession no. E-MTAB-8767) (56).
Proceedings of the National Academy of Sciences , résumé, 2020