The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

Zhou, Daoying; Duan, Zengqiang; Li, Zhenyu; Ge, Fangfang; Wei, Ran; Kong, Lingyun

doi:10.3389/fphar.2022.1091779

Cited by 66 publications

(21 citation statements)

References 99 publications

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“…An acidic environment is frequently observed in tumors due to the lack of oxygen ( 40 ). In addition, lactic acid, a metabolite of glycolysis, can also accumulate in the TME, leading to reduced extracellular pH ( 41 ). In these conditions, VISTA can potentially interact with specific ligands like PSGL-1.…”

Section: Discussionmentioning

confidence: 99%

A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

Iadonato,

Ovechkina,

Lustig

et al. 2023

Front. Immunol.

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BackgroundImmune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response.MethodsFully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and single B cell sequencing. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fc-effector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys.ResultsHere, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was well-tolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated.ConclusionThese results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors.

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Section: Discussionmentioning

confidence: 99%

A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

Iadonato,

Ovechkina,

Lustig

et al. 2023

Front. Immunol.

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“…The present study demonstrated that this requirement is significantly enhanced upon induction of mutant GNAS on a mutant Ras background. Increased glycolysis is generally related with tumor progression and aggressiveness via increased substrate production [32]. Lactate, which is the final product of glycolysis, can acidify the tumor microenvironment [32, 33].…”

Section: Discussionmentioning

confidence: 99%

“…Increased glycolysis is generally related with tumor progression and aggressiveness via increased substrate production [32]. Lactate, which is the final product of glycolysis, can acidify the tumor microenvironment [32, 33]. Tumor microenvironment acidification promotes proliferation, resistance to apoptosis, invasiveness, metastatic potential, and aggressiveness of tumor cells [34].…”

Section: Discussionmentioning

confidence: 99%

Metabolic Reprogramming by Mutant GNAS Creates an Actionable Dependency in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Makino,

Rajapakshe,

Selvanesan

et al. 2024

Preprint

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ObjectiveOncogenic “hotspot” mutations ofKRASandGNASare two major driver alterations in Intraductal Papillary Mucinous Neoplasms (IPMNs), which arebona fideprecursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specificKrasG12DandGnasR201Cco-expression in p48Cre;KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice (“Kras;Gnas” mice) caused development of cystic lesions recapitulating IPMNs. Here, we aim to unveil the consequences of mutantGnasR201Cexpression on phenotype, transcriptomic profile, and genomic dependencies.DesignWe performed multimodal transcriptional profiling (bulk RNA sequencing, single cell RNA sequencing, and spatial transcriptomics) in the “Kras;Gnas”autochthonous model and tumor-derived cell lines (Kras;Gnascells), whereGnasR201Cexpression is inducible. A genome-wide CRISPR/Cas9 screen was conducted to identify potential vulnerabilities inKrasG12D;GnasR201Cco-expressing cells.ResultsInduction ofGnasR201C– and resulting G(s)alpha signaling – leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genesGpi1andSlc2a1inKrasG12D;GnasR201Cco-expressing cells. Real-time metabolic analyses inKras;Gnascells and autochthonousKras;Gnasmodel confirmed enhanced glycolysis uponGnasR201Cinduction. Induction ofGnasR201CmadeKrasG12Dexpressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme PFKFB3 was a driver of increased glycolysis uponGnasR201Cinduction.ConclusionMultiple orthogonal approaches demonstrate thatKrasG12DandGnasR201Cco-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs.SUMMARYWhat is already known on this topicActivating “hotspot” mutations ofKRASandGNASare found in a majority of Intraductal Papillary Mucinous Neoplasms (IPMNs).Expression of mutantKRASandGNASdrives development of IPMN-like cystic lesions in the murine pancreas that eventually progress to pancreatic ductal adenocarcinoma (PDAC).What this study addsMutantGNASand the resulting aberrant G(s)alpha signaling drives a transcriptional signature of gastric (pyloric type) metaplasia in IPMNs with mucin production.Aberrant G(s)alpha signaling enhances glycolysis via protein kinase A-dependent phosphorylation of the glycolytic enzyme PFKFB3.Enhanced glycolysis inKRAS;GNAS-mutated IPMN cells is validated via multiple orthogonal approachesin vitroandin vivoand represents an actionable metabolic vulnerability.How this study might affect research, practice or policyThe present study provides mechanistic insight into how aberrant G(s)alpha signaling alters the biology ofKras-mutant pancreatic epithelial neoplasia through metaplastic and metabolic reprogramming.Targeting glycolysis in IPMNs may represent both a therapeutic avenue as well as an opportunity for intercepting progression to invasive cancer.

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“…The gene SLC7A5 promotes proliferation, migration, and invasion in gastric cancer [31], colorectal cancer [32], endometrial cancer [33], and breast cancer [34]. Furthermore, a pan-cancer survival analysis of SLC7A5, including 33 tumors in the GEPIA2 public database, also showed that high SLC7A5 expression signi cantly reduces survivals (Figure 5A).…”

Section: Mф-glioma Fusion Hybrids Exhibit Elevated Expression Of Mф-d...mentioning

confidence: 91%

Glioma Cells Achieve Malignant Progression by Fusion with Macrophages to Gain High SLC7A5 Expression

yuedong,

Li,

Liu

et al. 2024

Preprint

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Background Glioma is the most prevalent primary tumor of the central nervous system (CNS) in adults, and its high proliferative and invasive capacities are typically associated with a poor prognosis. Cell fusions are a crucial phenomenon in both physiological and pathological processes. Within tumors, tumor cells can acquire diverse gene expression profiles and undergo malignant progression through fusion events with themselves or other somatic cells. This process leads to the emergence of stem cell characteristics, drug resistance properties, immune evasion abilities, and enhanced migration and invasion capacities. Macrophages (MФs) represent the predominant cell type within glioma immune microenvironments and are important partners for fusion events with glioma cells. However, the biological characteristics and underlying mechanisms of MФ-glioma fusion hybrids remain incompletely elucidated. Results We validated the presence of MФ-glioma double positive cells through analysis of glioma single-cell RNA sequencing (scRNA-seq) data and examination of glioma specimens. We successfully established the MФ-glioma cell fusion hybrid models in vitro. Subsequent propidium iodide (PI) staining combined with flow cytometry analysis revealed a significant increase in the chromosome content of hybrid cells. Research on the biological characteristics of MФ-glioma fusion hybrids has revealed their heightened proliferation and invasion capabilities. Further mechanistic investigations have elucidated that SLC7A5, a tumor-associated gene originating from parental MФs, orchestrates the augmented proliferative and invasive capabilities of hybrid cells via activation of the mTOR-RPS6 signaling pathway. Furthermore, the MФ-glioma fusion hybrids exhibited heightened sensitivity to a specific inhibitor of SLC7A5 (JPH203) compared to their parental cells. Conclusion Glioma cells achieve malignant progression by acquiring high expression of the tumor-associated gene SLC7A5 through fusion with MФs. This discovery provides a new perspective on the malignant biology of gliomas.

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The significance of glycolysis in tumor progression and its relationship with the tumor microenvironment

Cited by 66 publications

References 99 publications

A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

Metabolic Reprogramming by Mutant GNAS Creates an Actionable Dependency in Intraductal Papillary Mucinous Neoplasms of the Pancreas

Glioma Cells Achieve Malignant Progression by Fusion with Macrophages to Gain High SLC7A5 Expression

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