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Metastatic Gastric Cancer Outcomes Informed by Single-Cell Transcriptome Profiles

NEW YORK – A University of Texas MD Anderson Cancer Center-led team has mapped out transcriptomic features of individual cells from a type of metastatic gastric cancer found in the peritoneal cavity, known as peritoneal carcinomatosis.

"[Peritoneal carcinomatosis] represents a major unmet clinical need, as we don't have effective treatment options available for these patients," co-senior and -corresponding author Jaffer Ajani, a gastrointestinal medical oncology researcher at MD Anderson Cancer Center, said in a statement. "Based on our findings, we need to move toward profiling these cells in each patient in order to offer more tailored treatment options."

As they reported in Nature Medicine on Monday, Ajani and his colleagues considered single-cell RNA sequence profiles for 45,048 individual peritoneal carcinomatosis cells from 15 people with gastric adenocarcinoma, using cell lineage and differentially expressed gene analyses to unearth a 12-gene expression signature that appeared to coincide with survival outcomes in the peritoneal carcinomatosis patients.

The researchers subsequently validated that prognostic signature — which appeared to divide the tumors into groups with "gastric-dominant" or "gastrointestinal-mixed" groups — using data for another 1,336 gastric adenocarcinoma cases considered for the Cancer Genome Atlas project and three other large research cohorts.

"The intriguing aspect is that, by classifying tumor cells based on lineage compositions, we noted two groups of patients," co-senior and -corresponding author Linghua Wang, a genomic medicine and biomedical sciences researcher at MD Anderson, said in a statement. "The more gastric-like [peritoneal carcinomatosis] cells had an aggressive phenotype and were associated with shorter survival. However, the more intestine-like [peritoneal carcinomatosis] cells were less aggressive, and patients had longer survival."

Along with the proposed prognostic signature, the team used its single-cell RNA-seq data and other molecular, genotypic, and phenotypic clues to examine the cell types and lineages contributing to peritoneal carcinomatosis formation and features, as well as the nature of the intra-tumoral heterogeneity behind the gastric adenocarcinoma tumors that metastasize to the peritoneal space.

While previous studies broadly suggested that high levels of intra-tumoral heterogeneity tended to mark gastric adenocarcinoma cases with poorer-than-usual outcomes, the investigators noted that the single-cell transcriptomic approach offered a closer look at prognostic contributors that will likely be bolstered by further research in this area. 

"This is an important first step toward a better understanding of the single-cell biology of these cancer cells, but we have more work to do," Ajani suggested in a statement. "We foresee that understanding this heterogeneity could one day be used to guide clinical decision making that is most beneficial to each patient."