The stomach is the main recipient of food and putrefaction of water and grain. With a complex structure, gastric is not only the digestive organ, but also an important endocrine organ. With the addition of multiple identities, the stomach often faces heavy crises. According to the World Health Organization data in 2022, there are more than 1 million new cases of gastric cancer worldwide. Among them, China has more than 500,000 cases, which is the number one incidence country of gastric cancer worldwide.

Therefore, precise understanding of the characteristics of gastric cancer patients and the mechanism of cancer progression is of great significance for the development of precise gastric cancer treatment. ScRNA-seq can analyze the characteristics of gastric cancer from multiple dimensions of "cellular and genetic" in a comprehensive and accurate way.

Features of gastric cancer

Gastric cancer is a malignant tumor that originates from epithelial tissues, and its pathogenesis often includes four processes: chronic superficial gastritis, chronic atrophic gastritis, intestinal dermal metaplasia, and carcinogenesis.

Gastric cancer has the characteristics of insidious onset and difficult early diagnosis. The symptoms of early gastric cancer are not obvious. Many people have no symptoms or only symptoms such as abdominal discomfort, so they do not pay attention to it. Only very few people will go to hospital for gastroscopy, so most patients are already in advanced stage when diagnosed, and the prognosis is poor. In addition, gastric cancer is also characterized by high heterogeneity. Gastric cancer has geographical differences, and patients in different regions show strong inter-tumor heterogeneity. By inter-tumor heterogeneity, it means that the tumors are different among different patients. In addition, the heterogeneity of gastric cancer is not only reflected between individuals, but also exists among the primary and metastatic foci of the same patient, which is what we call intratumoral heterogeneity.

It is because of this heterogeneity that gastric cancer patients face the problem of difficult treatment, and coupled with the limited targets for gastric cancer treatment, it is still a great challenge to achieve precise treatment.

What can single cell sequencing technology do in gastric cancer?

ScRNA-seq is able to study cell heterogeneity at single-cell resolution, and its unparalleled advantages bring new insights to the study of gastric cancer.

Then, what important information about gastric cancer can be obtained by single-cell sequencing technology in the process of gastric cancer development, diagnosis and treatment?

Aiding the diagnosis of gastric cancer

1. Explore gastric cancer progression mechanism to assist in disease diagnosis

2. 
   

 The rapid progression of gastric cancer, and how the cells are connected and changed during the rapid progression of early gastric cancer to advanced gastric cancer is an important part of analyzing the pathogenesis of gastric cancer, and understanding the characteristics of different progression stages of gastric cancer can assist in the diagnosis of gastric cancer.

For example, Li's team [1] performed scRNA-seq of gastric mucosa biopsies from gastric cancer patients to explore the expression patterns of different cell types in premalignant Lesion and early gastric cancer, and identified the OR51E1 gene as a unique feature of early -malignant lesions, which provides great clinical reference value for the early diagnosis of gastric cancer.

scRNA-seq explores gastric cancer progression mechanism

Tracing the etiology of gastric cancer

2. Dissect the heterogeneity of gastric cancer and the origin of tumor cells to trace the lineage

In-depth understanding of the origin of tumor cells of gastric cancer patients can better understand the tumor heterogeneity of patients and analyze the origin of gastric cancer from multiple dimensions, which can help improve the treatment strategy of gastric cancer and better carry out precise treatment.

The lineage composition of gastric cancer is significantly associated with patient survival, and understanding the  lineage origin of gastric cancer cells can help to speculate on the relevant factors affecting patient survival.

For example, Wang Linghua's team [2] performed scRNA-seq to trace the epithelial cell lineage in 10 long- survival and 10 short-survival advanced gastric cancer patients,  and found that the epithelial cells of advanced gastric cancer included "gastric-dominant" and " GI-mixed " cell types. After differential expression analysis, the 12-gene signature associated with poor prognosis was identified, which helped us understand gastric cancer more comprehensively and is undoubtedly of great value to achieve precise treatment of gastric cancer.

ScRNA-seq reveals the composition of gastric cancer cell lineage

Assessing the effect of treatment

3. Detection of dynamic changes in tumor microenvironment to assess tumor progression and the effect of drug therapy

The components of tumor microenvironment are complex and variable. In tumors, besides cancer cells, it also includes other cell types ，such as stromal cells 、 immune cells. When tumor cells occur in our body, immune cells will play the role of "guard" to monitor and destroy these tumor cells, so the proportion of immune cells fighting against cancer cells in tumor is higher at this time. As the tumor progresses, the number of tumor cells gradually increases, and the immune cells will gradually become weak.

ScRNA-seq to detect the dynamic changes of tumor microenvironment can help us to assess the progression of tumor and the effectiveness of drug therapy. For example, Lee's team [3] conducted single-cell study on tumors of advanced gastric cancer patients before and after chemotherapy and found that NK, tumor-associated macrophages decreased and effector T-cell infiltration increased in patients who responded to the drugs.

scRNA-seq resolves tumor heterogeneity and tumor microenvironment remodeling

Provide new targets for drug development

4. Exploring new targets for targeted therapies to develop new drugs

Targeted therapy is an important idea to achieve precise treatment and improve patient's therapeutic effect. Most of the so-called targeted therapies refer to the targeting of drugs, which can target the malignant phenotype of tumor cells and act on tumor-specific cell receptors, signaling pathways, etc., so as to inhibit tumor growth and proliferation or promote the process of tumor apoptosis.

As the structure of gastric cancer is complex, there are very few targets for drug therapy, so how to find more therapeutic targets is a major direction for the future precision treatment of gastric cancer. ScRNA-seq can not only uncover biomarkers for a certain cell population, but also predict the feasibility and therapeutic efficacy of drug targets.

Summary

As a "star" technology, scRNA-seq can help us more comprehensively analyze the heterogeneity of gastric cancer and the remodeling of gastric cancer tumor microenvironment, trace the origin of gastric cancer tumor cell lineage, explore the pathogenesis of gastric cancer from a new perspective, and discover new drug targets. This can not only assist physicians in individualized and precise treatment of gastric cancer, but also provide potential drug development targets for pharmaceutical companies and other institutions.

References

[1] Zhang P, Yang M, et al., Dissecting the Single-Cell Transcriptome Network Underlying Gastric Premalignant Lesions and Early Gastric Cancer. Cell Rep. 2019 May 7;27(6):1934-1947.e5. doi: 10.1016/j.celrep.2019.04.052.
[2] Wang R, Dang M, et al., Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma. Nat Med. 2021 Jan;27(1):141-151. doi: 10.1038/s41591-020-1125-8.
[3] Kim R, An M, et al., Early Tumor-Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer. Cancer Discov. 2022 Apr 1;12(4):984-1001. doi: 10.1158/2159-8290.CD-21-0888.