YTHDF2 orchestrates tumor-associated macrophage reprogramming and controls antitumor immunity through CD8 T cells.

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8 T cell-mediated antitumor immunity.

Cellular signals converge at the NOX2-SHP-2 axis to induce reductive carboxylation in cancer cells.

Environmental stresses, including hypoxia or detachment for anchorage independence, or attenuation of mitochondrial respiration through inhibition of electron transport chain induce reductive carboxylation in cells with an enhanced fraction of citrate arising through reductive metabolism of glutamine. This metabolic process contributes to redox homeostasis and sustains biosynthesis of lipids. Reductive carboxylation is often dependent on cytosolic isocitrate dehydrogenase 1 (IDH1).

Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.

Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E.

The loss of RNA N-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8 T cell dysfunction and tumor growth.

Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q TAMs are regulated by an RNA N-methyladenosine (mA) program and modulate tumor-infiltrating CD8 T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an mA methyltransferase Mettl14 drives CD8 T cell differentiation along a dysfunctional trajectory, impairing CD8 T cells to eliminate tumors.

Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases mA Methylation.

N-methyladenosine (mA) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of mA methylation in mRNA metabolism has been well documented recently, regulation of the mA machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the mA deposition.

Author Correction: 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

In the initial published version of this article, there was a mistake in the P value for the correlation between gene-expression changes and 5 hmC changes in tumors. The correct P value should be same as the P value shown in Fig. S6A: 9.

Author Correction: Anti-tumour immunity controlled through mRNA mA methylation and YTHDF1 in dendritic cells.

In this Letter, a citation to 'Fig. 1e' has been corrected to 'Fig. 1d' in the sentence starting "By contrast, the anti-tumour response…".

Anti-tumour immunity controlled through mRNA mA methylation and YTHDF1 in dendritic cells.

There is growing evidence that tumour neoantigens have important roles in generating spontaneous antitumour immune responses and predicting clinical responses to immunotherapies. Despite the presence of numerous neoantigens in patients, complete tumour elimination is rare, owing to failures in mounting a sufficient and lasting antitumour immune response. Here we show that durable neoantigen-specific immunity is regulated by mRNA N-methyadenosine (mA) methylation through the mA-binding protein YTHDF1.

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors.

Background: Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.

5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers.

DNA modifications such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks known to affect global gene expression in mammals. Given their prevalence in the human genome, close correlation with gene expression and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology, we report here the genome-wide profiling of 5hmC in circulating cell-free DNA (cfDNA) and in genomic DNA (gDNA) of paired tumor and adjacent tissues collected from a cohort of 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver or thyroid cancer and normal tissues from 90 healthy individuals.

TET-catalyzed 5-hydroxymethylcytosine regulates gene expression in differentiating colonocytes and colon cancer.

The formation of differentiated cell types from pluripotent progenitors involves epigenetic regulation of gene expression. DNA hydroxymethylation results from the enzymatic oxidation of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) 5-mC dioxygenase enzymes. Previous work has mapped changes in 5-mC during differentiation of intestinal stem cells.

Metformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population.

Background: Emerging evidence from observational studies has suggested that metformin may be beneficial in the primary prevention of colorectal cancer (CRC). However, to the authors' knowledge, none of these studies was conducted in a US population. Because environmental factors such as Western diet and obesity are implicated in the causation of CRC, a large case-control study was performed to assess the effects of metformin on the incidence of CRC in a US population.

Ultra-performance liquid chromatography and time-of-flight mass spectrometry analysis of ginsenoside metabolites in human plasma.

American ginseng is a commonly used herbal medicine in the United States. When ginseng is taken orally, its active components, ginsenosides, are reportedly biotransformed by intestinal microbiota. Previous pharmacokinetic evaluations of ginseng in humans have focused on its parent constituents.