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The tumor heterogeneity of breast cancer is very large, and these cells with different functions are very important for the determination of the etiology and treatment plan
.
Studies have found that tumor infiltrating lymphocytes (TIL) are biomarkers that respond well to neoadjuvant chemotherapy, and tumor-associated macrophages (TAM) are associated with poor prognosis and are new targets for tumor immunotherapy
.
In addition, mesenchymal cells have also become important drug resistance regulators, driving metastasis and anti-tumor immunity
.
However, the exact subclass of these cells is currently unclear
Single-cell RNA sequencing (scRNA-seq) can comprehensively and systematically map tumor cells, revealing cell biology, disease etiology, and drug response
.
Studies have applied scRNA-seq to human breast cancer, revealing the continuous differentiation state in TILs, the role of tissue-resident lymphocytes in triple-negative breast cancer (TNBC), and the chemotherapy resistance of tumor cells in TNBC
.
There is an urgent need for more detailed and high-resolution breast cancer cell maps to further determine the classification of breast cancer, identify cell heterogeneity and their interactions, and determine cell differentiation events
.
On September 6, 2021, the research team of the Gavin Institute of Medical Research in Australia published a research paper entitled "A single-cell and spatially resolved atlas of human breast cancer" in the journal Nature Genetics
.
Research has developed a single-cell method based on inherent subtype classification (SCSubtype) to reveal the heterogeneity of recurrent tumor cells, providing the most comprehensive picture of breast cancer cells so far
.
The study discovered a new population of PD-L1/PD-L2+ macrophages that are related to clinical outcomes
.
Mesenchymal cells can be divided into three different subgroups
The spatial transcriptome reveals the interaction between stromal cells and immune cells, and provides unique insights for anti-tumor immune regulation
.
Using single-cell characteristics to deconvolute a large breast cancer cohort, the stages are divided into 9 "ecotypes", which have unique cell composition and clinical results
.
First, in order to clarify the cellular structure of breast cancer, the research team analyzed three common clinical subtypes (estrogen receptor positive, ER+; human epidermal growth factor receptor 2 positive, HER2+; triple negative breast cancer, using scRNA-seq )
.
26 cases of primary tumors, and identified a type of malignant epithelial cells
Based on extensive transcriptome analysis using PAM50 gene markers, breast cancer is divided into five intrinsic molecular subtypes
.
However, the role of breast cancer molecular subtypes at the individual cell level is unclear
The results show that SCSubtype can reveal cell heterogeneity, correctly identify malignant cells, and has higher specificity than batch and scRNA-seq
.
Next, the research team studied the biological pathways that drive intratumoral transcriptional heterogeneity (ITTH) and generated 574 ITTH gene signatures
.
These gene characteristics identified 7 gene modules (GMs) with different functional characteristics
gm also reveals the heterogeneity of tumor cells
.
In general, the analysis of SCSubtype and gm provides a complementary new method for ITTH classification and further proves the huge heterogeneity of tumor cells
In order to detect the microenvironment of breast tumors with high resolution, the research team reclassified immune cells and stromal cells, and found 18 T cells, congenital lymphocyte clusters, 13 myeloid cell clusters, and 5 types of cancer in patients.
Fibroblast clusters, three endothelial cell clusters and three parietal cell clusters
.
Immune cell clusters of different clinical subtypes are different in nature, and the most appropriate targeting strategy needs to be formulated according to different clinical subtypes
.
They also found similar stromal cell clusters in different breast cancer subtypes and normal breast tissue samples, suggesting that stromal cell clusters may be resident cell types that undergo remodeling in the tumor environment
.
Spatial transcriptome analysis showed that related cell clusters of different clinical subtypes are mutually exclusive in spatial arrangement
.
Finally, based on the single-cell results and the large breast cancer cohort, the research team conducted a cluster analysis
The results showed that these 9 tumor clusters have similar cell composition, which is called "ecotype"
.
These ecotypes are related to tumor subtypes, sc subtype cell distribution and the diversity of main cell types, and the prognosis of each ecotype is significantly different
.
In general, this work defines the cellular atlas of breast cancer from three levels of single-cell RNA sequencing, spatial transcriptome and immunophenotype, reveals the new immunophenotype of breast cancer, and conducts a comprehensive review of breast cancer.
Classification
.
Cell models provide an important basis
.
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