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PNAS Papers on Gastric Cancer CircRNA, TNBC Drivers, Immune Cell Atlas

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted this week.

A team from the Chinese Academy of Sciences, the University of Science and Technology of China, and other centers explores circular RNA (circRNA) roles in gastric cancer. Based on RNA sequencing profiles for five gastric cancers and five normal matched samples from nearby sites, the researchers narrowed in on a circRNA known as CircURI1 that is formed through back-splicing of coding sequences for the URI1 gene and had enhanced expression in the gastric cancer samples. With a series of follow-up experiments, they saw signs that CircURI1 may help curb gastric cancer cell migration, invasiveness, and metastasis via alternative splicing effects stemming from its interactions with the heterogeneous nuclear ribonucleoprotein M (hnRNPM). "CircURI1 inhibited [gastric cancer] metastasis by sequestering hnRNPM protein to modulate alternative splicing of a small subset of genes involved in cell motility, intimating a potential self-preservation mechanism against tumor metastasis," the authors report.

Researchers in the US, China, UK, and Sweden search for triple-negative breast cancer drivers and tumor suppressors with RNA sequencing on matched tumor and normal-adjacent tissue samples from five women with TNBC. Along with higher-than-usual expression of several genes with known ties to the breast cancer subtype, the team also saw expression shifts for cytochrome P450 family (CYP) enzymes implicated in processes such as fatty acid activation or calcitriol or retinoic acid inactivation as well as significantly reduced expression of genes that interact with the estrogen receptor (ER)-beta, a proposed TNBC treatment target that is expressed in a subset of tumors. After exploring the results further using preserved TNBC samples, cell lines, and mouse experiments using patient-derived TNBC xenograft models, the authors suggest that "CYP-mediated pathways can be drivers of TNBC but that ER-beta is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ER-beta functionless on genes involved in proliferation and inflammation."

Both age and sex appear to influence the immune cells and pathways that are active in individuals' peripheral blood samples, according to a single-cell transcriptomics study by a team from Sun Yat-Sen University in China. With the help of barcoded single-cell small conditional RNA-seq on peripheral blood mononuclear samples from 20 participants — including five individuals apiece from "young female," "old female," "young male," and "old male" groups — the researchers saw a higher proportion of plasma cells and enhanced BAFF/APRIL signaling activity in the female participants compared with their male counterparts, as well as a reduced proportion of natural killer cells. Women from the younger group tended to have increased activity involving genes from T- and B-cell-related pathways, while inflammatory gene levels rose in older men. Across the board, monocyte levels notched up with age, while naïve T-cell levels declined. "Taken together," the authors conclude, "the results of this study have described the sex-based differences in multiple facets of the immune system, including the cellular composition, [differentially expressed genes], enriched pathways, and cell-cell communication, while also providing potential mechanisms for sex-based differences in diseases."