Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.

Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.

ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.

Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes-aldehyde dehydrogenase 1 family member 2 (ALDH1L2)-produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling.

Biomarkers of Drug Resistance in Temporal Lobe Epilepsy in Adults.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy in adults. Experimental and clinical data indicate that neuroinflammation and neurodegeneration accompanying epileptogenesis make a significant contribution to the chronicity of epilepsy and the development of drug resistance in TLE cases. Changes in plasma and serum concentrations of proteins associated with neuroinflammation and neurodegeneration can be predictive biomarkers of the course of the disease. This study used an enzyme-linked immunosorbent assay of the following plasma proteins: brain-derived neurotrophic factor (BDNF), tumor necrosis factor alpha (TNFa), and high-mobility group protein B1 (HMGB1) in patients with mesial TLE to search for biomarkers of the disease. The objective of the study was to examine biomarkers of the neuroinflammation and neurodegeneration of plasma: BDNF, TNFa, and HMGB1. The aim of the study was to identify changes in the concentration of circulating pro-inflammatory and neurotrophic factors that are prognostically significant for the development of drug resistance and the course of TLE. A decrease in the concentration of BDNF, TNFa, and HMGB1 was registered in the group of patients with TLE compared with the control group. A significant decrease in the concentration of HMGB1 in patients with drug-resistant TLE was observed. Aberrations in plasma concentrations of BDNF, TNFa, and HMGB1 in patients with TLE compared with the controls have been confirmed by earlier studies. A decrease in the expression of the three biomarkers may be the result of neurodegenerative processes caused by the long course of the disease. The results of the study may indicate the acceptability of using HMGB1 and TNFa as prognostic biological markers to indicate the severity of the disease course and the risk of developing drug resistance.

Supramolecular Amphiphiles Based on Pillar[5]arene and Meroterpenoids: Synthesis, Self-Association and Interaction with Floxuridine.

In recent years, meroterpenoids have found wide biomedical application due to their synthetic availability, low toxicity, and biocompatibility. However, these compounds are not used in targeted drug delivery systems due to their high affinity for cell membranes, both healthy and in cancer cells. Using the approach of creating supramolecular amphiphiles, we have developed self-assembling systems based on water-soluble pillar[5]arene and synthetic meroterpenoids containing geraniol, myrtenol, farnesol, and phytol fragments. The resulting systems can be used as universal drug delivery systems. It was shown by turbidimetry that the obtained pillar[5]arene/synthetic meroterpenoid systems do not interact with the model cell membrane at pH = 7.4, but the associates are destroyed at pH = 4.1. In this case, the synthetic meroterpenoid is incorporated into the lipid bilayer of the model membrane. The characteristics of supramolecular self-assembly, association constants and stoichiometry of the most stable pillar[5]arene/synthetic meroterpenoid complexes were established by UV-vis spectroscopy and dynamic light scattering (DLS). It was shown that supramolecular amphiphiles based on pillar[5]arene/synthetic meroterpenoid systems form monodisperse associates in a wide range of concentrations. The inclusion of the antitumor drug 5-fluoro-2'-deoxyuridine (floxuridine) into the structure of the supramolecular associate was demonstrated by DLS, 19F, 2D DOSY NMR spectroscopy.

CD157 and Brain Immune System in (Patho)physiological Conditions: Focus on Brain Plasticity.

Ectoenzyme and receptor BST-1/CD157 has been considered as a key molecule involved in the regulation of functional activity of cells in various tissues and organs. It is commonly accepted that CD157 catalyzes NAD+ hydrolysis and acts as a component of integrin adhesion receptor complex. Such properties are important for the regulatory role of CD157 in neuronal and glial cells: in addition to recently discovered role in the regulation of emotions, motor functions, and social behavior, CD157 might serve as an important component of innate immune reactions in the central nervous system. Activation of innate immune system in the brain occurs in response to infectious agents as well as in brain injury and neurodegeneration. As an example, in microglial cells, association of CD157 with CD11b/CD18 complex drives reactive gliosis and neuroinflammation evident in brain ischemia, chronic neurodegeneration, and aging. There are various non-substrate ligands of CD157 belonging to the family of extracellular matrix proteins (fibronectin, collagen I, finbrinogen, and laminin) whose activity is required for controlling cell adhesion and migration. Therefore, CD157 could control structural and functional integrity of the blood-brain barrier and barriergenesis. On the other hand, contribution of CD157 to the regulation of brain development is rather possible since in the embryonic brain, CD157 expression is very high, whereas in the adult brain, CD157 is expressed on neural stem cells and, presumably, is involved in the neurogenesis. Besides, CD157 could mediate astrocytes' action on neural stem and progenitor cells within neurogenic niches. In this review we will summarize how CD157 may affect brain plasticity acting as a molecule at the crossroad of neurogenesis, cerebral angiogenesis, and immune regulation.

Adapt and conquer: Metabolic flexibility in cancer growth, invasion and evasion.

BACKGROUND: It has been known for close to a century that, on average, tumors have a metabolism that is different from those found in healthy tissues. Typically, tumors show a biosynthetic metabolism that distinguishes itself by engaging in large scale aerobic glycolysis, heightened flux through the pentose phosphate pathway, and increased glutaminolysis among other means. However, it is becoming equally clear that non tumorous tissues at times can engage in similar metabolism, while tumors show a high degree of metabolic flexibility reacting to cues, and stresses in their local environment. SCOPE OF THE REVIEW: In this review, we want to scrutinize historic and recent research on metabolism, comparing and contrasting oncogenic and physiological metabolic states. This will allow us to better define states of bona fide tumor metabolism. We will further contextualize the stress response and the metabolic evolutionary trajectory seen in tumors, and how these contribute to tumor progression. Lastly, we will analyze the implications of these characteristics with respect to therapy response. MAJOR CONCLUSIONS: In our review, we argue that there is not one single oncogenic state, but rather a diverse set of oncogenic states. These are grounded on a physiological proliferative/wound healing program but distinguish themselves due to their large scale of proliferation, mutations, and transcriptional changes in key metabolic pathways, and the adaptations to widespread stress signals within tumors. We find evidence for the necessity of metabolic flexibility and stress responses in tumor progression and how these responses in turn shape oncogenic progression. Lastly, we find evidence for the notion that the metabolic adaptability of tumors frequently frustrates therapeutic interventions.