A 3D-printed SERS bionic taster for dynamic tumor metabolites detection.

The variation of tumor-associated metabolites in extracellular microenvironment timely reflects the development, the progression and the treatment of cancers. Conventional methods for metabolite detection lack the efficiency to grasp the dynamic metabolic alterations. Herein, we developed a SERS bionic taster which enabled real-time analysis of extracellular metabolites. The instant information of cell metabolism was provided by the responsive Raman reporters, which experienced SERS spectral changes upon metabolite activation. Such a SERS sensor was integrated into a 3D-printed fixture which fits the commercial-standard cell culture dishes, allowing in-situ acquisition of the vibrational spectrum. The SERS taster can not only accomplish simultaneous and quantitative analysis of multiple tumor-associated metabolites, but also fulfill the dynamic monitoring of cellular metabolic reprogramming, which is expected to become a promising tool for investigating cancer biology and therapeutics.

Advancements in Analyzing Tumor Metabolites through Chemical Derivatization-Based Chromatography.

Understanding the metabolic abnormalities of tumors is crucial for early diagnosis, prognosis, and treatment. Accurate identification and quantification of metabolites in biological samples are essential to investigate the relationship between metabolite variations and tumor development. Common techniques like LC-MS and GC-MS face challenges in measuring aberrant metabolites in tumors due to their strong polarity, isomerism, or low ionization efficiency during MS detection. Chemical derivatization of metabolites offers an effective solution to overcome these challenges. This review focuses on the difficulties encountered in analyzing aberrant metabolites in tumors, the principles behind chemical derivatization methods, and the advancements in analyzing tumor metabolites using derivatization-based chromatography. It serves as a comprehensive reference for understanding the analysis and detection of tumor metabolites, particularly those that are highly polar and exhibit low ionization efficiency.

ACAA1 Is a Predictive Factor of Survival and Is Correlated With T Cell Infiltration in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancers. KRAS mutation is the second most prevalent mutation in NSCLC. KRAS mutant cancer cells suppress the anti-tumor T cell response. However, the underlying mechanism is still unknown. Here, we analyzed the differential expression of acetyl-CoA acyltransferase 1 (ACAA1) in various types of cancers using the TIMER database and validated the results in the NSCLC cell line H1944. We silenced oncogenic KRAS by siRNA targeting KRASG13D, and employed an MAPK signaling pathway inhibitor to clarify the possible regulatory pathway. Moreover, we analyzed the correlation of ACAA1 expression level with B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells. Correlations between expression of ACAA1 and several biomarkers of mutation burden were also tested. Finally, we evaluated the prognostic value of ACAA1 in a wide range of cancers using the Kaplan-Meier Plotter Database. We found lower expression of ACAA1 in tumor tissue than in adjacent normal tissue in various cancers. This result was confirmed using a GEO dataset. Knock-down of mutant KRAS resulted in increased ACAA1 mRNA level in H1944 cells. ACAA1 mRNA level was significantly upregulated in H1944 after treatment with MAPK pathway inhibitor sorafenib, indicating that oncogenic KRAS may downregulate ACAA1 through MAPK signaling. ACAA1 was negatively correlated with biomarkers of tumor mutation burden, including BRCA1, ATM, ATR, CDK1, PMS2, MSH2, and MDH6. Conversely, ACAA1 expression was positively correlated with infiltrating CD4+ cells and with Th1, Th2, Treg cells in the lung tumor microenvironment. Finally, we showed that ACAA1 is a predictive factor for survival in several cancer types. In summary, decreased ACAA1 expression is correlated with poor prognosis and decreases immune infiltration of CD4+ T cells in LUAD and LUSC. ACAA1 also predicts T cell exhaustion in LUSC. The mechanism underlying KRAS/ACAA1 axis-mediated regulation of immune cell infiltration requires further investigation.

Metabolic profiling of the three neural derived embryonal pediatric tumors retinoblastoma, neuroblastoma and medulloblastoma, identifies distinct metabolic profiles.

The rare pediatric embryonal tumors retinoblastoma, medulloblastoma and neuroblastoma derive from neuroectodermal tissue and share similar histopathological features despite different anatomical locations and diverse clinical outcomes. As metabolism can reflect genetic and histological features, we investigated whether the metabolism of embryonal tumors reflects their similar histology, shared developmental and neural origins, or tumor location. We undertook metabolic profiling on 50 retinoblastoma, 39 medulloblastoma and 70 neuroblastoma using high resolution magic angle spinning magnetic resonance spectroscopy (1H-MRS). Mean metabolite concentrations identified several metabolites that were significantly different between the tumor groups including taurine, hypotaurine, glutamate, glutamine, GABA, phosphocholine, N-acetylaspartate, creatine, glycine and myoinositol, p < 0.0017. Unsupervised multivariate analysis found that each tumor group clustered separately, with a unique metabolic profile, influenced by their underlying clinical diversity. Taurine was notably high in all tumors consistent with prior evidence from embryonal tumors. Retinoblastoma and medulloblastoma were more metabolically similar, sharing features associated with the central nervous system (CNS). Neuroblastoma had features consistent with neural tissue, but also contained significantly higher myoinositol and altered glutamate-glutamine ratio, suggestive of differences in the underlying metabolism of embryonal tumors located outside of the CNS. Despite the histological similarities and shared neural metabolic features, we show that individual neuroectodermal derived embryonal tumors can be distinguished by tissue metabolic profile. Pathway analysis suggests the alanine-aspartate-glutamate and taurine-hypotaurine metabolic pathways may be the most pertinent pathways to investigate for novel therapeutic strategies. This work strengthens our understanding of the biology and metabolic pathways underlying neuroectodermal derived embryonal tumors of childhood.

Effect of IDH gene mutation on acute myeloid leukemia / 上海交通大学学报（医学版）

Isocitrate dehydrogenase (IDH) is an important metabolic enzyme involved in the tricarboxylic acid cycle. In recent years, IDH has become the most frequent tumor metabolic mutation gene in acute myeloid leukemia (AML). Unlike other mutations, it gains new functions which can catalyze α-ketoglutarate (α-KG) to produce the tumor metabolite D-2-hydroxyglutarate (D-2-HG). The increased D-2-HG in the cells can affect bone marrow cell differentiation and proliferation and induce myeloid tumors by the genetic controls, cell signaling, bone marrow microenvironment changes and other ways. Currently, the new IDH2 inhibitors AG-221 and IDH1 inhibitors become the first-line drugs targeted therapy in patients with IDH mutations in AML. This paper focused on the mutation of IDH and its mutation characteristics, the formation mechanism of AML by the metabolites produced by mutation, the metabolic pathway of tumor metabolites and the research progress of IDH inhibitors.