Glycolysis in the tumor microenvironment: a driver of cancer progression and a promising therapeutic target

Zhao, Junpeng; Jin, Dandan; Huang, Mengxiang; Ji, Jie; Xu, Xuebing; Wang, Fei; Zhou, Lirong; Bao, Baijun; Jiang, Feng; Xu, Weisong; Lu, Xiaomin; Xiao, Mingbing

doi:10.3389/fcell.2024.1416472

Cited by 4 publications

References 167 publications

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Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia

Buri,

Shoeb,

Bykov

et al. 2023

Preprint

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The term cancer immunoediting describes the dual role by which the immune system can both suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. While the importance of CD8+T cells in all three phases of cancer immunoediting is well-established, the role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a prominent role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+B acute lymphoblastic leukaemia cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoeditingin vitro. Whereas most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquiring resistance to NK cells. We found that the production of interferon-γ (IFN-γ) rather than direct cytotoxicity by NK cells, led to the emergence of highly resistant tumour cells. Besides the well-known upregulation of components involved in major histocompatibility complex I surface expression, we also found novel genes that had not previously been linked to NK cell resistance in leukaemic cells, such asLy6aandPlaat3. Our results demonstrate that tumour cells are actively edited during the equilibrium phase and use different avenues to escape NK cell-mediated eradication. Our findings provide a starting point to develop novel therapeutic approaches to treat tumours that have successfully evaded from NK cell surveillance and to convert them into a controllable disease.

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Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia

Buri,

Shoeb,

Bykov

et al. 2023

Preprint

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Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas

Makino,

Rajapakshe,

Chellakkan Selvanesan

et al. 2024

Gut

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BackgroundOncogenic ‘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.ObjectiveWe 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 tumour-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 signalling—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 onGnasR201Cinduction. Induction ofGnasR201CmadeKrasG12Dexpressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis onGnasR201Cinduction.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.

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Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

Rahman,

Yadab,

Ali

2024

Cells

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Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a “protective shield,” neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.

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Glycolysis in the tumor microenvironment: a driver of cancer progression and a promising therapeutic target

Cited by 4 publications

References 167 publications

Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia

Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia

Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas

Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy

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