Gastric adenocarcinoma is one of the most lethal cancers worldwide due to treatment resistance, and the cellular and molecular mechanisms involved in the progression from early pre-cancer to tumor formation are not fully understood. Now, a new study led by researchers at the University of Texas MD Anderson Cancer Center provides a deeper understanding of the evolution of the tumor microenvironment during cancer progression.

The findings are published in Cancer Cell in an article titled, “Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression.”

“Understanding tumor microenvironment (TME) reprogramming in gastric adenocarcinoma (GAC) progression may uncover novel therapeutic targets,” wrote the researchers. “Here, we performed single-cell profiling of precancerous lesions, localized and metastatic GACs, identifying alterations in TME cell states and compositions as GAC progresses. Abundant IgA+ plasma cells exist in the premalignant microenvironment, whereas immunosuppressive myeloid and stromal subsets dominate late-stage GACs.”

“Gastric adenocarcinoma exhibits a high degree of heterogeneity with respect to both its phenotypes and molecular characteristics, but research around it has lagged behind other cancer types,” explained Linghua Wang, MD, PhD, associate professor of genomic medicine. “Most studies have concentrated on tumor cells and largely overlooked the immune and stromal cells within the tumor microenvironment, which are very dynamic and play critical roles in cancer progression. This study represents the largest single-cell RNA sequencing cohort of gastric adenocarcinoma to date and brings important new insights into how these cell populations impact disease progression.”

The researchers obtained data from 68 gastric adenocarcinoma samples encompassing various disease stages through single-cell RNA sequencing (scRNA-seq).

Various immune and stromal cell subsets formed multicellular communities, or collections of cell states, present in the tumor microenvironment of an individual tumor sample. The research team termed these groups “ecotypes” and identified six unique ecotypes, with each dominated by specific immune and stromal cell states.

“While many published single-cell studies have focused on characterizing the heterogeneity of each individual cell compartment, our study utilized a novel approach and concept of integrating various components of the tumor microenvironment to define ecotypes and investigated their clinical significance,” Wang said. “This approach can readily be applied to studies in other cancer types.”

The researchers discovered two ecotypes (EC3 and EC6) correlated with different histological, genomic, and clinical features of primary gastric adenocarcinomas. Tumors categorized as EC3 were composed mainly of immune cell subsets, whereas EC6 tumors predominantly included stromal cell subsets. Patients with EC6 tumors had more aggressive disease and significantly shorter survival compared to those with EC3 tumors.

The study also identified SDC2 as a potential target. SDC2 overexpression in stromal cells was correlated with aggressive disease and advanced stages. In addition, SDC2 expression was consistently elevated in stromal cells across various 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 every step of the way in their clinical journey,” said Jaffer Ajani, MD, professor of gastrointestinal medical oncology. “Our team strives to use novel interrogations to discover new therapeutic targets to improve the outcomes of these patients. While there are many questions left to answer, targeting SDC2 in cancer-associated fibroblasts represents a potentially exciting avenue that warrants further investigation.”

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