Tumor-derived G-CSF induces an immunosuppressive microenvironment in an osteosarcoma model, reducing response to CAR.GD2 T-cells.

Sarcomas are rare, mesenchymal tumors, representing about 10-15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.

N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.

Background: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases.

Hindering NAT8L expression in hepatocellular carcinoma increases cytosolic aspartate delivery that fosters pentose phosphate pathway and purine biosynthesis promoting cell proliferation.

N-acetylaspartate (NAA) is synthesized by the mitochondrial enzyme NAT8L, which uses acetyl-CoA and aspartate as substrates. These metabolites are fundamental for bioenergetics and anabolic requirements of highly proliferating cells, thus, NAT8L modulation may impinge on the metabolic reprogramming of cancer cells. Specifically, aspartate represents a limiting amino acid for nucleotide synthesis in cancer.

Adaptive antioxidant response to mitochondrial fatty acid oxidation determines the proliferative outcome of cancer cells.

Alterations in lipid catabolism have been broadly described in cancer cells and show tumor-type specific effects on proliferation and cell survival. The factor(s) responsible for this heterogeneity is currently unknown and represents the main limitation in the development of therapeutic interventions that impair lipid metabolism. In this study, we focused on hexanoic acid, a medium-chain fatty acid, that can quickly boost oxidative metabolism by passively crossing mitochondrial membranes.

Lipid Catabolism and ROS in Cancer: A Bidirectional Liaison.

Although cancer cell metabolism was mainly considered to rely on glycolysis, with the concomitant impairment of mitochondrial metabolism, it has recently been demonstrated that several tumor types are sustained by oxidative phosphorylation (OXPHOS). In this context, endogenous fatty acids (FAs) deriving from lipolysis or lipophagy are oxidised into the mitochondrion, and are used as a source of energy through OXPHOS. Because the electron transport chain is the main source of ROS, cancer cells relying on fatty acid oxidation (FAO) need to be equipped with antioxidant systems that maintain the ROS levels under the death threshold.

Aconitase 2 sensitizes MCF-7 cells to cisplatin eliciting p53-mediated apoptosis in a ROS-dependent manner.

Aconitase 2 (ACO2) belongs to the tricarboxylic acid (TCA) cycle, which represents a key metabolic hub for cellular metabolism that is frequently altered in cancer for satisfying bioenergetic and biosynthetic requirements of proliferating cells. The promotion of ACO2 activity in breast cancer cell lines was shown to slow down proliferation imposing a switch from aerobic glycolysis to oxidative metabolism. The alteration of metabolic pathways in cancer also impinges on the sensitivity to chemotherapeutic interventions.