2023-09-03 18:08:27
MD Anderson Cancer Center researchers have uncovered key dynamics of the gastric adenocarcinoma tumor microenvironment, identifying SDC2 as a promising new therapeutic target.
A study by MD Anderson provides insight into the progression of gastric cancer and highlights a potential therapeutic target.
A recent study by scientists at the University of Texas MD Anderson Cancer Center offers new insights into how the tumor microenvironment changes during the development of gastric cancer. Highlights of the study, published in cancer cellinclude a link between multicellular communities and patient outcomes, as well as a promising new therapeutic target.
Gastric adenocarcinoma is among the deadliest cancers in the world, mainly due to its natural resistance to treatment. However, the cellular and molecular processes that lead to the transition from early precancerous stages to tumor formation and metastasis remain largely unclear. This study sheds light on how different subsets of immune and stromal cells change throughout the progression of gastric cancer.
Linghua Wang, MD, Ph.D. Credit: MD Anderson Cancer Center
The study was conducted by Linghua Wang, MD, Ph.D., associate professor of genomic medicine, in collaboration with Jaffer Ajani, MD, professor of gastrointestinal medical oncology, and Ruiping Wang, Ph.D., researcher postdoctoral fellow at Wang Lab. .
“Gastric adenocarcinoma shows a high degree of heterogeneity in both its phenotypes and molecular characteristics, but research on this topic lags behind other types of cancer,” Wang said. “Most studies have focused on tumor cells and have largely overlooked the immune and stromal cells of the tumor microenvironment, which are very dynamic and play a critical role in cancer progression. This study represents the largest cohort single-cell RNA sequencing study of gastric adenocarcinoma to date and provides important new insights into the impact of these cell populations on disease progression.
By obtaining single-cell RNA sequencing (scRNA-seq) data from 68 gastric adenocarcinoma specimens encompassing various disease stages – including precancerous lesions, localized tumors and distant metastases – as well as specimens from normal tissues and peripheral blood, the team characterized the various immune systems and stromal cell populations within the tumor microenvironment and discovered actionable targets to modulate the tumor microenvironment.
New approach allows researchers to dissect complex tumor microenvironment
Various immune and stromal cell subsets formed multicellular communities, or sets of cell states, present in the tumor microenvironment of an individual tumor sample. The research team called these groups “ecotypes” and identified six unique ecotypes, each dominated by specific immune and stromal cell states.
“While many published single-cell studies have focused on characterizing the heterogeneity of each individual cellular compartment, our study used a new approach and concept of integrating various components of the tumor microenvironment to define ecotypes and study their clinical significance,” Wang said. “This approach can easily be applied to studies of other types of cancer. »
A notable finding is that two ecotypes (EC3 and EC6) correlated with different histological, genomic, and clinical features of primary gastric adenocarcinomas. EC3-graded tumors were primarily composed of immune cell subsets, while EC6 tumors were primarily comprised of stromal cell subsets. Patients with EC6 tumors had more aggressive disease and significantly shorter survival than those with EC3 tumors.
The results indicate SDC2 as a potential therapeutic target in stromal cells
While stromal components of the tumor microenvironment play crucial roles in tumor initiation, progression, and metastasis, cancer treatment strategies have so far rarely focused on modulating stromal components, especially in patients with gastric adenocarcinoma.
This study identified SDC2 as a potential target deserving of further investigation. The researchers found SDC2 overexpression in stromal cells, particularly in cancer-associated fibroblasts, was correlated with aggressive disease and advanced stages, and strongly associated with adverse survival outcomes. Furthermore, SDC2 expression was consistently elevated in stromal cells from a variety of other cancer types, including pancreatic cancer, colorectal cancer, bladder cancer, breast cancer, and clear cell renal cell carcinoma.
“There are unmet needs for patients with gastric adenocarcinoma at every stage of their clinical journey,” Ajani said. “Our team is working to use new interrogations to discover new therapeutic targets to improve outcomes for these patients. Although there are still many unanswered questions, targeting SDC2 in cancer-associated fibroblasts represents a potentially exciting avenue that merits further investigation.
The research team shared their results with the wider research community through the online single-cell research portal developed by the Wang Lab.
This research was supported by MD Anderson, National Cancer Institute (R01CA266280, CA016672), University Cancer Foundation, Andrew Sabin Family Foundation, Department of Defense (CA160445), Stupid Strong Charitable Foundation, Schecter Private Foundation, River Creek Foundation, V Foundation for Cancer Research, John Armstrong Fund, Golfers Against Cancer, Inc., Zeus Immunology Research Fund, Kevin Fund, Myer Fund, Dio Fund, Milrod Fund, Caporella Fund for Gastric Cancer Research, as well as the Dallas, Sultan, Park, Smith, Frazier, Oaks, Vanstekelenberg, Planjery, McNeil, Moran, Hyland, Weede and Cantu families.
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