Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer

Liao, Zi-Xian; Kempson, Ivan M.; Hsieh, Chia Chen; Tseng, S-Ja; Yang, Pan‐Chyr

doi:10.1016/j.drudis.2021.07.014

Cited by 34 publications

(38 citation statements)

References 55 publications

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“…In summary, glycolysis may be critical for the prognosis and treatment of COAD patients. As a signaling molecule, glycolysis-generated lactate can be released into the extracellular environment, which is closely related to tumor metastasis, poor prognosis and recurrence ( Perez-Tomas and Perez-Guillen, 2020 ; Liao et al, 2021 ). Therefore, identifying highly sensitive and specific biomarkers related to glycolysis- and lactate-related genes is a promising therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

Identification of a glycolysis- and lactate-related gene signature for predicting prognosis, immune microenvironment, and drug candidates in colon adenocarcinoma

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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Background: Colon adenocarcinoma (COAD), a malignant gastrointestinal tumor, has the characteristics of high mortality and poor prognosis. Even in the presence of oxygen, the Warburg effect, a major metabolic hallmark of almost all cancer cells, is characterized by increased glycolysis and lactate fermentation, which supports biosynthesis and provides energy to sustain tumor cell growth and proliferation. However, a thorough investigation into glycolysis- and lactate-related genes and their association with COAD prognosis, immune cell infiltration, and drug candidates is currently lacking.Methods: COAD patient data and glycolysis- and lactate-related genes were retrieved from The Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases, respectively. After univariate Cox regression analysis, a nonnegative matrix factorization (NMF) algorithm was used to identify glycolysis- and lactate-related molecular subtypes. Least absolute shrinkage and selection operator (LASSO) Cox regression identified twelve glycolysis- and lactate-related genes (ADTRP, ALDOB, APOBEC1, ASCL2, CEACAM7, CLCA1, CTXN1, FLNA, NAT2, OLFM4, PTPRU, and SNCG) related to prognosis. The median risk score was employed to separate patients into high- and low-risk groups. The prognostic efficacy of the glycolysis- and lactate-related gene signature was assessed using Kaplan–Meier (KM) survival and receiver operating characteristic (ROC) curve analyses. The nomogram, calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC) were employed to improve the clinical applicability of the prognostic signature. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on differentially expressed genes (DEGs) from the high- and low-risk groups. Using CIBERSORT, ESTIMATE, and single-sample GSEA (ssGSEA) algorithms, the quantities and types of tumor-infiltrating immune cells were assessed. The tumor mutational burden (TMB) and cytolytic (CYT) activity scores were calculated between the high- and low-risk groups. Potential small-molecule agents were identified using the Connectivity Map (cMap) database and validated by molecular docking. To verify key core gene expression levels, quantitative real-time polymerase chain reaction (qRT–PCR) assays were conducted.Results: We identified four distinct molecular subtypes of COAD. Cluster 2 had the best prognosis, and clusters 1 and 3 had poor prognoses. High-risk COAD patients exhibited considerably poorer overall survival (OS) than low-risk COAD patients. The nomogram precisely predicted patient OS, with acceptable discrimination and excellent calibration. GO and KEGG pathway enrichment analyses of DEGs revealed enrichment mainly in the “glycosaminoglycan binding,” “extracellular matrix,” “pancreatic secretion,” and “focal adhesion” pathways. Patients in the low-risk group exhibited a larger infiltration of memory CD4+ T cells and dendritic cells and a better prognosis than those in the high-risk group. The chemotherapeutic agent sensitivity of patients categorized by risk score varied significantly. We predicted six potential small-molecule agents binding to the core target of the glycolysis- and lactate-related gene signature. ALDOB and APOBEC1 mRNA expression was increased in COAD tissues, whereas CLCA1 and OLFM4 mRNA expression was increased in normal tissues.Conclusion: In summary, we identified molecular subtypes of COAD and developed a glycolysis- and lactate-related gene signature with significant prognostic value, which benefits COAD patients by informing more precise and effective treatment decisions.

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Section: Introductionmentioning

confidence: 99%

Identification of a glycolysis- and lactate-related gene signature for predicting prognosis, immune microenvironment, and drug candidates in colon adenocarcinoma

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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“… 12 , 14 , 15 Previously, we developed matrix-incorporated LOX for the depletion of lactate, which has been implicated in the potentially beneficial repolarization of macrophages. 12 , 14 , 15 …”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, tumor-secreted lactate acts as a significant regulator that modulates the immune system. 12 Furthermore, the consumption of tumor-secreted lactate has been implicated in the beneficial polarization of macrophages. 14 , 15 In our studies, GM-CSF combined with LOX exhibited a higher level of M1 macrophages ( Figure 3 ) than GM-CSF alone, leading to an expressively improved proportion of M1 macrophages.…”

Section: Discussionmentioning

confidence: 99%

“… 13 Specifically, lactate can promote the suppressive functions of the M2-like polarization of tumor-associated macrophages and subsequently promote tumor growth. 12 , 14 Overall, the depletion of lactate through lactate oxidase (LOX) activity has been implicated in the potentially beneficial repolarization of macrophages. 14 , 15 We hypothesized that if the GM-CSF produced by cancer cells infected with a recombinant adeno-associated virus (AAV2) combined with LOX can recruit M1 macrophages, then the inhibition of cancer cell proliferation can be improved ( Figure 1 A).…”

Section: Introductionmentioning

confidence: 99%

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Macrophage Distribution Affected by Virus-Encoded Granulocyte Macrophage Colony Stimulating Factor Combined with Lactate Oxidase

Hsieh

Wang

et al. 2022

ACS Omega

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Oncolytic virotherapy was approved as a localized treatment for advanced melanoma by the US Food and Drug Administration (FDA) in 2015. Granulocyte macrophage colony stimulating factor (GM-CSF) encoded by clinical virus-infected tumor cells, acting as a pro-inflammatory cytokine or growth factor, increases tumor antigen presentation, leading to the activation of macrophages and T cells. Notably, tumor-secreted lactate can promote the suppressive functions of M2-polarized tumor-associated macrophages and subsequently promote tumor growth. Furthermore, the consumption of tumor-secreted lactate has been implicated in the beneficial polarization of macrophages. Here, we report that GM-CSF-encoded recombinant adeno-associated virus (AAV2-GM-CSF) infection in B16-F10 mouse melanoma cells combined with lactate oxidase (LOX) leads to the recruitment of M1 macrophages for the inhibition of cancer cell growth. This study suggests that GM-CSF combined with LOX has potential as cancer virotherapy.

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“…The accumulation of lactate provides an acidic microenvironment that benefits tumor growth and progression. Besides, lactate produced by aerobic glycolysis can be secreted into the extracellular environment as a signaling molecule to regulate intercellular interactions ( Liao et al, 2021 ). In gastric cancer, lactate derived from tumor cells mediates the up-regulation of BDNF expression in cancer-associated fibroblasts by activating the NF-κB pathway, eventually resulting in acquired resistance ( Jin et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma

et al. 2022

Front. Cell Dev. Biol.

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Hepatocellular carcinoma (HCC) is the main subtype of primary liver cancer with high malignancy and poor prognosis. Metabolic reprogramming is a hallmark of cancer and has great importance on the tumor microenvironment (TME). As an abundant metabolite, lactate plays a crucial role in cancer progression and the immunosuppressive TME. Nonetheless, the potential roles of lactate in HCC remain unclear. In this study, we downloaded transcriptomic data of HCC patients with corresponding clinical information from the TCGA and ICGC portals. The TCGA-HCC dataset used as the training cohort, while the ICGC-LIRI-JP dataset was served as an external validation cohort. Cox regression analysis and the LASSO regression model were combined to construct the lactate metabolism-related gene signature (LMRGS). Then, we assessed the clinical significance of LMRGS in HCC. Besides, enriched molecular functions, tumor mutation burden (TMB), infiltrating immune cells, and immune checkpoint were comprehensively analyzed in different LMRGS subgroups. In total, 66 differentially expressed lactate metabolism-related genes (LMRGs) were screened. The functions of LMRGs were mainly enriched in mitochondrial activity and metabolic processes. The LMRGS comprised of six key LMRGs (FKTN, PDSS1, PET117, PUS1, RARS1, and RNASEH1) had significant clinical value for independently predicting the prognosis of HCC patients. The overall survival and median survival of patients in the LMRGS-high group were significantly shorter than in the LMRGS-low group. In addition, there were differences in TMB between the two LMRGS subgroups. The probability of genetic mutations was higher in the LMRGS-high group. Most importantly, the LMRGS reflected the TME characteristics. In the LMRGS-high group, the immune microenvironment presented a suppressed state, accompanied by more inhibitory immune cell infiltration, including follicular helper T cells and regulatory T cells. Additionally, the expression of inhibitory checkpoint molecules was much higher in the LMRGS-high group. Our study suggested that the LMRGS was a robust biomarker to predict the clinical outcomes and evaluate the TME of patients with HCC.

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Potential therapeutics using tumor-secreted lactate in nonsmall cell lung cancer

Cited by 34 publications

References 55 publications

Identification of a glycolysis- and lactate-related gene signature for predicting prognosis, immune microenvironment, and drug candidates in colon adenocarcinoma

Identification of a glycolysis- and lactate-related gene signature for predicting prognosis, immune microenvironment, and drug candidates in colon adenocarcinoma

Macrophage Distribution Affected by Virus-Encoded Granulocyte Macrophage Colony Stimulating Factor Combined with Lactate Oxidase

A Novel Lactate Metabolism-Related Gene Signature for Predicting Clinical Outcome and Tumor Microenvironment in Hepatocellular Carcinoma

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