【Nature Subjournal】Tang Fuyi/Wang Jie's team revealed tumor heterogeneity of small cell lung cancer through single-cell transcriptomic spectrometry

This article is the original of the translational medicine network, please indicate the source when reprinting

Author: Mia

Small cell lung cancer (SCLC) accounts for only 15%-20% of lung malignancies, but it is the most aggressive and lethal subtype
of lung cancer.
Therefore, we urgently need to have a better understanding of
its biology.
Recently, a research team has used single-cell sequencing technology to analyze individual cells within the tumor microenvironment (TME) and study their role
in the carcinogenic process.

On October 5, the team of Professor Tang Fuzhi of the School of Life Sciences of Peking University and the team of Professor Wang Jie of the Chinese Academy of Medical Sciences jointly published a report entitled "Single-cell transcriptomic profiling reveals the tumor heterogeneity of small-cell lung" at Signal Transduction and Targeted Therapy cancer" research paper.

The study performed a high-precision single-cell transcriptome analysis of approximately 5,000 single cells of primary tumors (PTs) and matched the normal adjacent tissues (NATs) of 11 SCLC patients, including one with both PT and recurrent tumors (RT
).
This comparative study reveals an immunosuppressive landscape
of SCLC in humans.

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Research background

 01 

Small cell lung cancer (SCLC) is a highly aggressive type of malignancy characterized by rapid growth and early development of widespread metastasis and acquired radiotherapy and chemotherapy resistance
.
In the past few decades, due to its poor prognosis and minimal improvement in treatment, it has been characterized as a refractory malignancy
.
Recently, SCLC therapy has achieved initial milestones
by incorporating immune checkpoint inhibitors into chemotherapy.
However, only a small number of patients benefit
from these immune-based treatments.
In addition, there are currently no reliable biomarkers that can accurately predict clinical outcomes
.

Although SCLC has long been considered a genetically homogeneous malignant with almost universal deletions of TP53 and RB1, eight recent transcriptome analysis studies have shown that the classification of molecular subtypes is based on the relative expression
of ASCL1, NEUROD1, POU2F3, YAP1, and other key transcription factors (TFs).
In addition, these subtypes have been shown to mediate different vulnerabilities and therapeutic targets, thereby facilitating the development
of subtype-specific drug screening and clinical therapeutic research.

Despite the large number of results achieved, most of these studies have focused on intertumor-tumor heterogeneity at the tumor cell body level, limiting the exploration
of intratumor heterogeneity (ITH) and interactions between different cellular components in the SCLC tumor microenvironment (TME).
There is substantial evidence that ITH between malignant and non-malignant cells and their interactions within TME are critical
for different aspects of tumor biology and treatment response.

Single-cell RNA sequencing (scRNA-seq) technology provides an opportunity to analyze cellular components in TME and study their role
in tumorigenesis and development.
Unlike standard large-population sequencing, which only provides an average, scRNA-seq is able to distinguish all cell types in complex populations, including malignant cells, immune cells, and stromal cells
in TME.
In addition, ITH of these cell types and the interactions between these multicellular components can also be further studied
by scRNA-seq.

However, while single-cell transcriptomic analysis has been performed on most cancer types, there are still no scRNA-seq studies
on matched primary tumors (PTs), normal lung tissue near tumors (NAT), and recurrent tumors (RTs).

Research overview

 02 

The researchers modified single-cell-labeled reverse transcription sequencing (STRT-seq) of fresh samples of primary lung tissue and matched adjacent normal lung tissue in 11 SCLC patients, revealing the heterocytic structure
of this malignant cancer at single-cell resolution.

scRNA-seq analysis of SCLC landscapes

The study data also revealed that malignant cells have heterogeneous expression procedures related to characteristics such as cell cycle, immunity, hypoxia, and EMT
.
Cell cycle procedures account for a large proportion of all SCLC patients, which explains why SCLC patients always benefit from radiation therapy and chemotherapy aimed at highly proliferating cell populations
.
Other relatively stationary cells have different transcriptional procedures that can lead to treatment resistance and tumor recurrence, providing actionable targets for combination therapy strategies for current treatment regimens
.
The researchers also observed that in longitudinal samples of PTs and RTs after surgical treatment, cell cycle procedures were always present, while other procedures underwent state switching or evolution
during tumor recurrence.

SCLC has been subtype classification
based on the expression of key transcriptional regulators at the overall level.
However, the classification and characterization of SCLC subtypes is still ongoing, especially at single-cell resolution
.
The scRNA-seq results of the study revealed patterns of co-expression or mutual exclusion of key transcription factors, the most common being ASCL1 and NEUROD1
.
The in-depth excavation of intratumoral heterogeneity (ITH) in different subtypes allows scientists to identify relevant biomarkers and signaling pathways, paving the way
for optimizing current treatments and developing new combination therapies.

Research summary

 03 

As part of a pilot study of ITH using single-cell sequencing techniques to characterize SCLC, the study still has some limitations
.
The sample size studied was relatively small, with only one matching primary and recurrent tumor, thus limiting the scope of
analysis.
In addition, more in vitro and in vivo studies are needed to further decipher the relationship between
ITH and the clinicopathological features of SCLC.

In summary, the study provides unbiased, high-precision scRNA-seq analysis of TME in human SCLC as a basis for
guiding treatment protocol design.

Resources:

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Note: This article is intended to introduce medical research advances and cannot be used as a reference for
treatment options.
For health guidance, please visit a regular hospital
.

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