Wang Jie/Tang Fuqun/Hejie found that mixed lineage cancer cells are widely present in lung cancer patients!

Lung cancer is one of the malignant tumors with the highest morbidity and mortality in the worl.

On August 13, 2022, the team of Pro.

The study has 4 key findings:

Discovery of a new class of mixed lineage tumor cells that are ubiquitous in all non-small cell lung cancer patient.

The researchers used high-precision single-cell transcriptome sequencing technology to analyze data from 19 patients with primary non-small cell lung cancer (14 adenocarcinoma, 3 squamous cell carcinoma, 1 composite small cell lung cancer, 1 mixed adenocarcinoma and neuronal carcinoma.

FigureExpression of different tumor subtype marker genes of lung cancer in epithelial cell.

In the past, single-cell transcriptome sequencing data based on the 10x Genomics platform have often been difficult to identify such mixed lineage tumor cells due to the relatively high doubles rate (double-cell confounding rate) and cross-contamination rat.

FigureMultiplex immunofluorescence staining and multiplex RNA in situ hybridization of adenocarcinoma marker gene NKX2-1 and squamous cell carcinoma marker gene TP63 in lung cancer tissu.

It was found that mixed-lineage tumor cells and classical single-lineage tumor cells in the same non-small cell lung cancer patient were derived from common tumor precursor cell.

The generation of mixed lineage tumor cells may be related to the abnormal differentiation of tumor cells, revealing the origin relationship between mixed lineage tumor cells and single lineage tumor cells in the same patient is the basis for understanding the plasticity of mixed lineage tumor cell.

FigureSingle-cell mitochondrial mutations and chromosomal copy number variation in different types of tumor cell.

Due to the limited number of sequenced cells and the detected mitochondrial mutation sites in this study, the specific progression direction of mixed-lineage tumor cells and single-lineage tumor cells is still unclear, but the researchers speculate that in a patient with non-small cell lung cancer, the most likely The key point is that first normal epithelial cells of a specific lineage are transformed into single-lineage tumor cells during early carcinogenesis, and then some of the tumor cells are further transformed into mixed-lineage tumor cells, gaining stronger cellular plasticit.

The proportion and characteristics of mixed lineage tumor cells were found to be closely related to the poor prognosis of patients with non-small cell lung cance.

Mixed lineage tumor cells have molecular features of two or even three different lung cancer tumor subtypes at the same time, suggesting that they have strong cellular plasticity and a higher gene expression program disorder, which is likely to be the cause of clinical treatment failure and tumor recurrence in non-small cell lung cance.

FigureAnalysis of survival curves of patients with lung adenocarcinoma and lung squamous cell carcinom.

Identify a group of marker genes that are highly expressed in mixed lineage tumor cells, and verify the function of AKR1B1 gene among the.

This study identified 73 marker genes that were specifically highly expressed in mixed-lineage tumor cells relative to single-lineage tumor cells, including interstitial-related genes FN1, TGFBI, COL1A1, and epithelial cell differentiation-related genes AKR1B1, SPRR1B, and keratin Genes KRT6A, KRT19, KRT17,et.

FigureFunctional studies of the mixed lineage tumor cell marker gene AKR1B1.

In summary, this study used high-precision single-cell transcriptome sequencing technology to deeply analyze the molecular characteristics of tumor cells in 16 human primary non-small cell lung cancer patients, and found a new type of mixed lineage tumor cell.
Mixed lineage tumor cells are widespread in patients with non-small cell lung cance.
It was further confirmed that in the same non-small cell lung cancer patient, mixed-lineage tumor cells and single-lineage tumor cells were derived from common tumor precursor cell.
This suggests that mixed-lineage tumor cells are highly plastic and may easily switch phenotypes between single-lineage and mixed-lineage states, providing a possible explanation for the relapse-prone and drug-resistant clinical characteristics of NSCL.
This study provides new clues for more accurate subtypes of non-small cell lung cancer, and has important guiding significance for the diagnosis and treatment of non-small cell lung cancer patients with high mixed lineage characteristics in the futur.

Li Qingqing and D.
Wang Rui, postdoctoral fellows from the School of Life Sciences of Peking University, and D.
Yang Zhenlin from the Cancer Hospital of the Chinese Academy of Medical Sciences are the co-first authors of the pape.
Pro.
Tang Fuchou from the Biomedical Frontier Innovation Center (BIOPIC) of Peking University, Pro.
Wang Jie and Academician He Jie from the Cancer Hospital of the Chinese Academy of Medical Sciences are the co-corresponding authors of the pape.
Supported by the National Science Foundation of China, the Beijing Natural Science Foundation, and the Innovation Team Development Program of the Ministry of Educatio.

Paper link:

https://genomemedicin.
biomedcentra.
com/articles/11186/s13073-022-01089-9