bims-stacyt 2022-04-24 papers

Cell Res. 2022 Apr 22.

SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors.

Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment. In this study, we discover that R-2-HG produced by IDH1-mutant tumor cells is preferentially imported into vascular endothelial cells and remodels mitochondrial respiration to promote tumor angiogenesis, conferring a therapeutic vulnerability in IDH1-mutant solid tumors. Mechanistically, SLC1A1, a Na+-dependent glutamate transporter that is preferentially expressed in endothelial cells, facilitates the influx of R-2-HG from the tumor microenvironment into the endothelial cells as well as the intracellular trafficking of R-2-HG from cytoplasm to mitochondria. R-2-HG hijacks SLC1A1 to promote mitochondrial Na+/Ca2+ exchange, which activates the mitochondrial respiratory chain and fuels vascular endothelial cell migration in tumor angiogenesis. SLC1A1 deficiency in mice abolishes mIDH1-promoted tumor angiogenesis as well as the therapeutic benefit of mIDH1 inhibitor in solid tumors. Moreover, we report that HH2301, a newly discovered mIDH1 inhibitor, shows promising efficacy in treating IDH1-mutant cholangiocarcinoma in preclinical models. Together, we identify a new role of SLC1A1 as a gatekeeper of R-2-HG-mediated crosstalk between IDH1-mutant tumor cells and vascular endothelial cells, and demonstrate the therapeutic potential of mIDH1 inhibitors in treating IDH1-mutant solid tumors via disrupting R-2-HG-promoted tumor angiogenesis.

DOI: https://doi.org/10.1038/s41422-022-00650-w

J Clin Endocrinol Metab. 2022 Apr 20. pii: dgac239. [Epub ahead of print]

Amino acid metabolism and protein turnover in lean and obese humans during exercise ─ effect of IL-6 receptor blockade.

Beckey Trinh, Merel Peletier, Casper Simonsen, Peter Plomgaard, Kristian Karstoft, Bente Klarlund Pedersen, Gerrit van Hall, Helga Ellingsgaard.

CONTEXT: IL-6 is implicated in skeletal muscle wasting and in regulating skeletal muscle hypertrophy in the healthy state.OBJECTIVE: To determine the role of IL-6 in regulating systemic protein and amino acid metabolism during rest, exercise and recovery in lean and obese humans.
PARTICIPANTS AND METHODS: In a non-randomized, single-blind design, twelve lean and nine obese individuals were infused first with 0.9% saline (Saline), secondly with the IL-6 receptor antibody tocilizumab (Acute IL-6R ab) and 21 days later with saline while still under tocilizumab influence (Chronic IL-6R ab). Outcome measures were determined before, during and after 90min exercise at 40% Wattmax by isotope dilution technique, using primed continuous infusion of L-[ring-D5]phenylalanine and L-[D2]tyrosine.
MAIN OUTCOME MEASURES: Systemic protein turnover and plasma amino acid concentrations.
RESULTS: We saw no effect of acute or chronic IL-6 receptor blockade on protein turnover. In lean individuals, chronic IL-6 receptor blockade increased plasma concentrations of total amino acids (rest Δ+186 μmol/l, 95%-CI [40;332]; recovery Δ+201 μmol/l, 95%-CI [55;347]) and essential amino acids (rest Δ+43 μmol/l, 95%-CI [12;76]; recovery Δ+45 μmol/l, 95%-CI [13;77]) independently of exercise but had no such effect in obese individuals (total amino acids rest Δ+63 μmol/l, 95%-CI [-170;295], recovery Δ-23 μmol/l, 95%-CI [-256;210]; essential amino acids rest Δ+26 μmol/l, 95%-CI [-21;73], recovery Δ+11 μmol/l, 95%-CI [-36;58]).
CONCLUSIONS: IL-6 receptor blockade has no effect on protein turnover in fasting lean and obese humans during rest, exercise and recovery. Chronic IL-6 receptor blockade increases total and essential amino acid concentrations only in lean individuals.

Keywords: IL-6; exercise; obese; protein turnover; recovery; rest; tocilizumab

DOI: https://doi.org/10.1210/clinem/dgac239

J Innate Immun. 2022 Apr 20. 1-17

GDF15 Suppresses Lymphoproliferation and Humoral Autoimmunity in a Murine Model of Systemic Lupus Erythematosus.

Georg Lorenz, Andrea Ribeiro, Ekatharina von Rauchhaupt, Vivian Würf, Christoph Schmaderer, Clemens D Cohen, Twinkle Vohra, Hans-Joachim Anders, Maja Lindenmeyer, Maciej Lech.

Growth and differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β superfamily, has been associated with acute and chronic inflammatory conditions including autoimmune disease, i.e., type I diabetes and rheumatoid arthritis. Still, its role in systemic autoimmune disease remains elusive. Thus, we studied GDF15-deficient animals in Fas-receptor intact (C57BL/6) or deficient (C57BL/6lpr/lpr) backgrounds. Further, lupus nephritis (LN) microdissected kidney biopsy specimens were analyzed to assess the involvement of GDF15 in human disease. GDF15-deficiency in lupus-prone mice promoted lymphoproliferation, T-, B- and plasma cell-expansion, a type I interferon signature, and increased serum levels of anti-DNA autoantibodies. Accelerated systemic inflammation was found in association with a relatively mild renal phenotype. Splenocytes of phenotypically overall-normal Gdf15-/- C57BL/6 and lupus-prone C57BL/6lpr/lpr mice displayed increased in vitro lymphoproliferative responses or interferon-dependent transcription factor induction in response to the toll-like-receptor (TLR)-9 ligand CpG, or the TLR-7 ligand Imiquimod, respectively. In human LN, GDF15 expression was downregulated whereas type I interferon expression was upregulated in glomerular- and tubular-compartments versus living donor controls. These findings demonstrate that GDF15 regulates lupus-like autoimmunity by suppressing lymphocyte-proliferation and -activation. Further, the data indicate a negative regulatory role for GDF15 on TLR-7 and -9 driven type I interferon signaling in effector cells of the innate immune system.

Keywords: Autoantibodies; Autoimmunity; Growth and differentiation factor 15; Inflammation; Lupus nephritis; Macrophages; Toll-like-receptor

DOI: https://doi.org/10.1159/000523991

Cell Death Dis. 2022 Apr 19. 13(4): 370

Leukemia inhibitory factor drives glucose metabolic reprogramming to promote breast tumorigenesis.

Xuetian Yue, Jianming Wang, Chun-Yuan Chang, Juan Liu, Xue Yang, Fan Zhou, Xia Qiu, Vrushank Bhatt, Jessie Yanxiang Guo, Xiaoyang Su, Lanjing Zhang, Zhaohui Feng, Wenwei Hu.

LIF, a multifunctional cytokine, is frequently overexpressed in many types of solid tumors, including breast cancer, and plays an important role in promoting tumorigenesis. Currently, how LIF promotes tumorigenesis is not well-understood. Metabolic reprogramming is a hallmark of cancer cells and a key contributor to cancer progression. However, the role of LIF in cancer metabolic reprogramming is unclear. In this study, we found that LIF increases glucose uptake and drives glycolysis, contributing to breast tumorigenesis. Blocking glucose uptake largely abolishes the promoting effect of LIF on breast tumorigenesis. Mechanistically, LIF overexpression enhances glucose uptake via activating the AKT/GLUT1 axis to promote glycolysis. Blocking the AKT signaling by shRNA or its inhibitors greatly inhibits glycolysis driven by LIF and largely abolishes the promoting effect of LIF on breast tumorigenesis. These results demonstrate an important role of LIF overexpression in glucose metabolism reprogramming in breast cancers, which contributes to breast tumorigenesis. This study also reveals an important mechanism underlying metabolic reprogramming of breast cancers, and identifies LIF and its downstream signaling as potential therapeutic targets for breast cancers, especially those with LIF overexpression.

DOI: https://doi.org/10.1038/s41419-022-04820-x