A groundbreaking study led by experts at The University of Texas MD Anderson Cancer Center reveals new perspectives on the evolving tumor microenvironment in gastric adenocarcinoma, signposting SDC2 as a potential avenue for future treatments.
The research from MD Anderson Cancer Center deepens our comprehension of gastric cancer’s evolution and unveils a likely candidate for targeted therapy.
The latest investigation by scientists at The University of Texas MD Anderson Cancer Center has added fresh dimensions to our understanding of alterations in the tumor microenvironment throughout the course of gastric cancer. Key features of this research, published in the scientific journal Cancer Cell, include associations between multicellular clusters and patient survival rates, as well as a promising new locus for therapeutic intervention.
Gastric adenocarcinoma is one of the most fatal types of cancer globally, primarily due to its inherent treatment resistance. Despite this, there is limited understanding of the cellular and molecular mechanisms governing the shift from precancerous phases to full-blown tumor growth and dissemination. The present study elucidates the variations in different immune and stromal cell types during the various stages of gastric cancer.
The research was orchestrated by Linghua Wang, M.D., Ph.D., an associate professor of Genomic Medicine, in collaboration with Jaffer Ajani, M.D., a professor of Gastrointestinal Medical Oncology, and Ruiping Wang, Ph.D., a postdoctoral researcher in the Wang Laboratory.
“Gastric adenocarcinoma is marked by extensive variability in both its phenotypic expressions and molecular traits; however, previous investigations have been predominantly focused on the tumor cells, largely neglecting the dynamic immune and stromal cells within the tumor microenvironment, which are instrumental in the course of the disease,” stated Wang. “This work is distinguished as the largest dataset of single-cell RNA sequencing for gastric adenocarcinoma to date, and it offers novel insights into the influence of these cellular populations on the disease’s trajectory.”
By conducting single-cell RNA sequencing (scRNA-seq) on 68 samples of gastric adenocarcinoma, covering precancerous growths, localized tumors, and distant metastases — alongside healthy tissue and blood samples — the team was able to characterize the variegated immune and stromal cellular populations within the tumor microenvironment. This enabled the identification of new targets for altering the tumor microenvironment.
A Novel Methodology Dissects the Intricacies of the Tumor Microenvironment
The research identified multiple immune and stromal cell subsets that coalesce to form multicellular assemblies, termed “ecotypes,” within an individual tumor sample’s microenvironment. Six unique ecotypes were identified, each dominated by distinct immune and stromal cellular configurations.
“Our study adopts a groundbreaking approach by integrating multiple aspects of the tumor microenvironment to categorize ecotypes, and explores their clinical implications,” Wang noted. “This strategy could be universally applied to research on other types of cancer.”
Two ecotypes, EC3 and EC6, exhibited a correlation with divergent histological, genomic, and clinical attributes of primary gastric adenocarcinomas. Tumors classified under EC3 were primarily composed of immune cell subsets, whereas EC6 was predominantly stromal in nature. Patients with EC6 tumors had a more aggressive disease course and notably shorter lifespan compared to those categorized under EC3.
Emerging Data Indicate SDC2 as a Viable Target for Stromal Cell Therapy
While stromal elements within the tumor microenvironment are crucial for cancer onset, progression, and spread, there has been little focus on therapeutic strategies targeting these stromal components, particularly in the context of gastric adenocarcinoma. The study identifies SDC2 as a potential area for further exploration, noting its overexpression in stromal cells, particularly in cancer-associated fibroblasts, was linked to aggressive disease progression and unfavorable patient outcomes. Moreover, SDC2 expression was consistently elevated in various other cancers, such as pancreatic, colorectal, bladder, breast, and clear cell renal cell carcinoma.
“In the clinical landscape of gastric adenocarcinoma, there remain numerous gaps in patient care,” Ajani said. “Our team is committed to utilizing innovative research methods to uncover new therapeutic opportunities that could enhance patient outcomes. While more work is needed, focusing on SDC2 in cancer-associated fibroblasts presents a promising direction for future studies.”
The study was supported by numerous foundations and institutions, including MD Anderson, the National Cancer Institute, the University Cancer Foundation, among others, and its findings have been made publicly available via the online Single-Cell Research Portal developed by the Wang Lab.
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Frequently Asked Questions (FAQs) about Gastric Adenocarcinoma Research
What is the main focus of the study conducted by MD Anderson Cancer Center?
The study primarily focuses on understanding the dynamics of the tumor microenvironment in gastric adenocarcinoma. It aims to identify new therapeutic targets and offers a deeper understanding of the disease’s progression.
Who led the research and who were the key collaborators?
The research was led by Linghua Wang, M.D., Ph.D., an associate professor of Genomic Medicine. Key collaborators included Jaffer Ajani, M.D., a professor of Gastrointestinal Medical Oncology, and Ruiping Wang, Ph.D., a postdoctoral researcher in the Wang Laboratory.
What is SDC2 and why is it significant?
SDC2 is identified as a promising new therapeutic target. Its overexpression in stromal cells, particularly in cancer-associated fibroblasts, was found to be associated with aggressive disease and unfavorable patient outcomes.
What are ecotypes as mentioned in the study?
Ecotypes refer to multicellular assemblies formed by various immune and stromal cell subsets within the tumor microenvironment. The study identified six unique ecotypes, each dominated by specific immune and stromal cell states.
How did the researchers gather their data?
The researchers obtained single-cell RNA sequencing (scRNA-seq) data from 68 samples of gastric adenocarcinoma, covering different stages of the disease including precancerous lesions, localized tumors, and distant metastases.
What are the potential clinical implications of this study?
The study has significant clinical implications as it highlights SDC2 as a promising therapeutic target. Additionally, it notes that tumors categorized under certain ecotypes have different levels of aggression and survival outcomes, which could influence treatment strategies.
How has the research been funded?
The research received support from multiple organizations, including MD Anderson, the National Cancer Institute, the University Cancer Foundation, and several other private foundations and family funds.
Is the research data publicly available?
Yes, the research team has shared their results with the wider research community through the online Single-Cell Research Portal developed by the Wang Lab.
What types of cancer could potentially benefit from targeting SDC2?
Besides gastric adenocarcinoma, elevated SDC2 expression was observed in other cancer types such as pancreatic, colorectal, bladder, breast, and clear cell renal cell carcinoma, indicating a broader applicability for targeting SDC2.
