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Mapping Paths Toward Targeted Therapeutics With Stomach Cancer Atlas

The world’s largest analysis of gastric tumours provides a launchpad for scientists to better understand gastric cancer growth and metastasis for more effective therapies.

According to a 2020 report by Globocan, gastric cancer is the fifth most frequently diagnosed malignancy and the fourth leading cause of cancer mortality worldwide. In Singapore, the disease is considered to be a significant cause of death, particularly among males. However, because gastric cancer is prevalent in Asia and relatively rare in the West, little is known about its driving pathways compared to other cancers.

To help scientists better understand gastric cancer and navigate paths to more effective therapies, scientists in Singapore have assembled the world’s largest and highest-resolution atlas of gastric cancer. The atlas, at the level of single cells, is expected to provide an essential reference for experts and shed new insights into how tumours differ from one another across patients by identifying the molecular pathways that drive gastric cancer growth and metastasis.

The research was led by Duke-NUS Medical School and the Agency for Science, Technology and Research (A*STAR)’s Genome Institute of Singapore (GIS), and involved collaborators from the National University Health System (NUHS), A*STAR’s Singapore Immunology Network (SIgN) and Institute of Molecular and Cell Biology (IMCB), the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS), and Kumamoto University, Japan.

“Patients with gastric cancer—also referred to as stomach cancer—are notoriously difficult to treat because we lack a clear understanding of the types of cells that make up their tumours,” said the study’s principal investigator, Professor Patrick Tan, from Duke-NUS’s Cancer & Stem Cell Biology Programme and GIS. “With precision oncology, cutting-edge technologies like single-cell sequencing can analyse patient cancers at unprecedented depth and resolution, to tailor therapies for patients, and reveal new pathways to improve diagnoses and treatments.”

As part of the Singapore Gastric Cancer Consortium, the research team gathered 31 patients at various stages of the disease and collected 46 tumour samples, from which they analysed 200,000 cells to assess their gene expression patterns. Their investigation led them to identify 34 distinct cell types including rare cell populations which had not been previously detected in gastric tumours. In addition, the scientists also observed that tumours from different patients exhibit different proportions and compositions of these cells. This may explain why similar treatments can lead to very different outcomes across patients.

Furthermore, since immune cells, particularly antibody-producing B cells, were discovered in some types of gastric tumours, the researchers believe that cancer immunotherapy could be used to tackle the disease. Besides immune cells, the team found that fibroblasts may be a key factor in driving gastric cancer, thereby suggesting that targeting these cells could open a new avenue for treatment.

“This work puts the power of single-cell sequencing to very effective use by creating the first in-depth map of cell types in stomach cancer. Now that we have the ‘parts list’, we can identify the vulnerabilities of these tumours and start to target them,” said Dr. Shyam Prabhakar, Associate Director, Spatial and Single Cell Systems, GIS.

Currently, the team is examining how the cell populations identified in the study change over time – whether changes are observed during early cancer development or due to drug treatment – in hopes of discovering new exploitable pathways for early cancer detection and drug development. The group will also collaborate with other researchers working on other cancer types to compile data and identify cell populations that contribute to multiple cancers.

“This study is important because it provides new insights into how gastric cancer develops. It is the most comprehensive study of its kind using advanced research technologies. Excitingly, our study identified some novel drug targets that may pave the way for new treatment strategies,” said Professor Jimmy So, Head and Senior Consultant at the National University Hospital (NUH)’s Division of General Surgery (Upper Gastrointestinal Surgery). He is also Professor of Surgery at NUS Yong Loo Lin School of Medicine (NUS Medicine), and the Head and Senior Consultant at the Division of Surgical Oncology, National University Cancer Institute, Singapore. [APBN]

Source: Kumar et al. (2021). Single-cell atlas of lineage states, tumor microenvironment and subtype-specific expression programs in gastric cancer. Cancer Discovery, candisc.0683.2021.