NEW YORK – A research team from the US and China has spelled out transcriptomic changes in the tumor microenvironment that happen during gastric cancer development and progression, highlighting key gene expression shifts and prognostically informative tumor microenvironment "ecotypes" in the process.
As they reported in Cancer Cell on Thursday, the researchers conducted single-cell RNA sequencing on almost 77,400 cells in precancerous, primary tumor, and metastatic tumor samples from 43 individuals with gastric adenocarcinoma, as well as in matched normal gastric tissue, cancer-free tissue near tumors, and peripheral blood samples.
Although gastric adenocarcinoma can develop from certain conditions such as chronic atrophic gastritis, they explained, the molecular events behind this progression and later metastatic events remain relatively murky.
"This study represents the largest single-cell RNA sequencing cohort of gastric adenocarcinoma to date," senior author Linghua Wang, a genomic medicine researcher at the University of Texas MD Anderson Cancer Center, said in a statement, "and brings important new insights into how these cell populations impact disease progression."
Using their single-cell transcriptome data, the team tracked gene expression changes occurring across different stages of cancer progression, focusing on features found in stromal and immune cells from the tumor microenvironment.
"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," Wang said.
When they characterized the cell types found in the tumor microenvironment before and after cancer development, the investigators saw changes in T cells and other immune cells. The microenvironment of precancerous lesions tended to have enhanced levels of plasma cells that secreted immunoglobulin A (IgA), for example. On the other hand, cells surrounding advanced, late-stage tumors tended to include myeloid and stromal cells that dampen down immune system activity.
"This study provides a detailed view of immune and stromal cell evolution within [gastric adenocarcinoma] progression and reveals potential targets for further investigation," the authors explained, "while also providing valuable resources for future research."
Based on cell type clusters they quantified, the team also defined three cellular ecosystems and six ecotypes that distinguished the microenvironments of blood, non-cancerous tissue, precancerous lesion, primary tumor, and metastatic tumor samples.
"Each ecosystem/ecotype was dominated by specific cell types/states, showing unique cellular compositions and cohabitation patterns," the authors explained. "This supports the notion that the discovered ecosystems/ecotypes can collectively capture the landscape of [tumor microenvironment] transcriptional heterogeneity across these tissue types."
With the help of published gene expression profiles for a larger set of primary gastric tumors, meanwhile, the researchers found that two tumor environment ecotypes — those found in primary tumor samples — tracked with other clinical features such as tumor pathology, genomic profiles, molecular subtype patterns, and patient outcomes.
Specifically, the team linked shorter survival times and more aggressive forms of the disease to a primary tumor microenvironment ecotype marked by a strong presence of stromal cells, among other features. A second ecotype found in primary tumor samples had pronounced immune cell representation and tended to correspond to longer survival times and distinct tumor subtype features.
The investigators also obtained prognostic clues from the cancer-associated fibroblasts in the stromal component of the microenvironment. In the original cell set and in follow-up analyses on additional gastric adenocarcinoma samples, they uncovered elevated expression of the SDC2 gene and protein in cancer-associated fibroblasts from individuals with aggressive disease and shorter survival. Likewise, cancer-associated fibroblasts that overexpressed SDC2 seemed to boost tumor growth in the team's subsequent xenograft tumor experiments in mice.
"While there are many questions left to answer, targeting SDC2 in cancer-associated fibroblasts represents a potentially exciting avenue that warrants further investigation," co-corresponding author Jaffer Ajani, a researcher at MD Anderson, said in a statement, noting that "[t]here are unmet needs for patients with gastric adenocarcinoma every step of the way in their clinical journey."