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The role of the serine/glycine metabolic pathway (SGP) has recently been demonstrated in tumors; however, the pathological relevance of the SGP in thyroid cancer remains unexplored. Here, we perform metabolomic profiling of 17 tumor-normal pairs; bulk transcriptomics of 263 normal thyroid, 348 papillary, and 21 undifferentiated thyroid cancer samples; and single-cell transcriptomes from 15 cases, showing the impact of mitochondrial one-carbon metabolism in thyroid tumors. High expression of serine hydroxymethyltransferase-2 (SHMT2) and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is associated with low thyroid differentiation scores and poor clinical features. A subpopulation of tumor cells with high mitochondrial one-carbon pathway activity is observed in the single-cell dataset. SHMT2 inhibition significantly compromises mitochondrial respiration and decreases cell proliferation and tumor size in vitro and in vivo. Collectively, our results highlight the importance of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer and suggest that SHMT2 is a potent therapeutic target.

Cellular dynamics and fate decision in early human embryogenesis remain largely unknown owing to the challenges of performing studies in human embryos.sup.1. Here, we explored whole-genomes of 334 single-cell colonies and targeted deep sequences of 379 bulk tissues obtained from various anatomical locations of seven recently deceased adult human donors. Using somatic mutations as an intrinsic barcode, we reconstructed early cellular phylogenies that demonstrate (1) an endogenous mutational rate that is higher in the first cell division but decreases to approximately one per cell per cell division later in life; (2) universal unequal contribution of early cells to embryo proper, resulting from early cellular bottlenecks that stochastically set aside epiblast cells within the embryo; (3) examples of varying degrees of early clonal imbalances between tissues on the left and right sides of the body, different germ layers and specific anatomical parts and organs; (4) emergence of a few ancestral cells that will substantially contribute to adult cell pools in blood and liver; and (5) presence of mitochondrial DNA heteroplasmy in the fertilized egg. Our approach also provides insights into the age-related mutational processes and loss of sex chromosomes in normal somatic cells. In sum, this study provides a foundation for future studies to complete cellular phylogenies in human embryogenesis. Adult human tissues from diverse sites around the body are used to reconstruct cellular phylogenies from early development, using somatic mutations as an internal barcode., Author(s): Seongyeol Park [sup.1] [sup.2] , Nanda Maya Mali [sup.3] , Ryul Kim [sup.1] , Jeong-Woo Choi [sup.3] [sup.4] , Junehawk Lee [sup.5] , Joonoh Lim [sup.1] , Jung Min [...]

Objective: To demonstrate the immune landscape of blood and synovial cells in the setting of ankylosing spondylitis (AS) through the analysis of both single‐cell transcriptome and surface protein expression, and to unveil the molecular characteristics of pathogenic Th17 cells. Methods: This study included 40 individuals with active AS, 20 individuals with stable AS, 40 patients with active rheumatoid arthritis, and 20 healthy controls. Surface phenotype and intracellular staining were assessed using flow cytometry after peripheral blood mononuclear cells and synovial fluid mononuclear cells were stimulated with T cell receptor. Single‐cell transcriptomes of 6 patients with active AS were studied along with cellular indexing of transcriptomes and epitopes by sequencing. We also assessed the outcome of targeting OX40 and glucocorticoid‐induced tumor necrosis factor receptor (GITR) on the surface of Th17 cells in a mouse model of curdlan‐injected SKG mice in which anti‐GITR ligand and/or anti‐OX40 ligand were used. Results: We identified pathogenic Th17 cells as polyfunctional interleukin‐17A (IL‐17A)– and interferon‐γ (IFNγ)–producing memory CD4+ T cells, with clinically supportive evidence for their pathogenic roles at sites of inflammation in AS. Transcriptome and flow cytometric analyses revealed that the coexpression of TNFRSF4 (OX40) and TNFRSF18 (GITR) is increased in pathogenic Th17 cells. Suppression of ligand receptor interactions in vivo through OX40 and GITR effectively suppressed clinical arthritis and decreased pathogenic Th17 cells in the curdlan‐injected SKG mouse model. Conclusion: Our results have implications for the understanding of pathogenic Th17 cells in AS patients and suggest potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The polycomb protein MEL-18 has been proposed as a tumor suppressor in breast cancer; however, its functional relevance to the hormonal regulation of breast cancer remains unknown. Here, we demonstrated that MEL-18 loss contributes to the hormone-independent phenotype of breast cancer by modulating hormone receptor expression. In multiple breast cancer cohorts, MEL-18 was markedly downregulated in triple-negative breast cancer (TNBC). MEL-18 expression positively correlated with the expression of luminal markers, including estrogen receptor-[alpha] (ER- [alpha], encoded by ESR1). MEL-18 loss was also associated with poor response to antihormonal therapy in ER-[alpha]-positive breast cancer. Furthermore, whereas MEL-18 loss in luminal breast cancer cells resulted in the downregulation of expression and activity of ER-[alpha] and the progesterone receptor (PR), MEL-18 overexpression restored ER-[alpha] expression in TNBC. Consistently, in vivo xenograft experiments demonstrated that MEL-18 loss induces estrogen-independent growth and tamoxifen resistance in luminal breast cancer, and that MEL-18 overexpression confers tamoxifen sensitivity in TNBC. MEL-18 suppressed SUMOylation of the ESR1 transactivators p53 and SP1, thereby driving ESR1 transcription. MEL-18 facilitated the deSUMOylation process by inhibiting BMI-1/RING1B- mediated ubiquitin-proteasomal degradation of SUMO1/sentrin-specific protease 1 (SENP1). These findings demonstrate that MEL-18 is a SUMO-dependent regulator of hormone receptors and suggest MEL-18 expression as a marker for determining the antihormonal therapy response in patients with breast cancer., Introduction Estrogen receptor-[alpha] (ER-[alpha]), a hormone-dependent nuclear receptor encoded by ESR1, is the most common clinical marker used for breast cancer prognosis and the classification of breast cancer subtypes. Approximately [...]