Liquid biopsy-based single-cell metabolic phenotyping of lung cancer patients for informative diagnostics

Ziming Li,Liu Yang,Chunying Wang,Min Xue,Jie Chen,Wei Wei,Baojun Wu,Qihui Shi,Xiang Lu,Shun Lu,Zhili Guo,Yin Tang,Yu Dong,Zhuo Wang

doi:10.1038/s41467-019-11808-3

Abstract

Accurate prediction of chemo- or targeted therapy responses for patients with similar driver oncogenes through a simple and least-invasive assay represents an unmet need in the clinical diagnosis of non-small cell lung cancer. Using a single-cell on-chip metabolic cytometry and fluorescent metabolic probes, we show metabolic phenotyping on the rare disseminated tumor cells in pleural effusions across a panel of 32 lung adenocarcinoma patients. Our results reveal extensive metabolic heterogeneity of tumor cells that differentially engage in glycolysis and mitochondrial oxidation. The cell number ratio of the two metabolic phenotypes is found to be predictive for patient therapy response, physiological performance, and survival. Transcriptome analysis reveals that the glycolytic phenotype is associated with mesenchymal-like cell state with elevated expression of the resistant-leading receptor tyrosine kinase AXL and immune checkpoint ligands. Drug targeting AXL induces a significant cell killing in the glycolytic cells without affecting the cells with active mitochondrial oxidation.

Highlights

Accurate prediction of chemo- or targeted therapy responses for patients with similar driver oncogenes through a simple and least-invasive assay represents an unmet need in the clinical diagnosis of non-small cell lung cancer
We develop and employ an on-chip metabolic cytometry (OMC) platform and fluorescent metabolic probes to perform metabolic phenotyping on the rare disseminated tumor cells (DTCs) in pleural effusions across a cohort of 32 lung adenocarcinoma (LADC) patients that covers prevalent driver oncogenes and molecular subtypes[25]
As demonstrated in our previous report[22], we developed an OMC assay for highthroughput screening of rare metabolically active tumor cells in liquid biopsy samples through exploiting the elevated glucose metabolism of the malignant cells compared to benign cells

Summary

Introduction

Accurate prediction of chemo- or targeted therapy responses for patients with similar driver oncogenes through a simple and least-invasive assay represents an unmet need in the clinical diagnosis of non-small cell lung cancer. The focus on genetic alterations may not fully explain the fact that some NSCLC patients have diverse responses to EGFR-TKIs even if they bear the same EGFR sensitive driver oncogenes and do not concurrently have other resistance-leading mutations[4]. A successful drug engagement is normally accompanied by the reduction of the aberrant glycolytic activity of tumor cells with a potential metabolic program switch to mitochondrial oxidation[5,6]. Such rapid inhibition on glycolysis, assessed by [18F]fluorodeoxyglucose (FDG) uptake through positron emission tomography (PET), has been utilized as an in vivo predictive biomarker of drug response for brain cancer[7]

Methods

Results

Conclusion