MCT4-Dependent Lactate Secretion Suppresses Antitumor Immunity in LKB1-Deficient NSCLC

Qian, Yu; Galán-Cobo, Ana; Guijarro, Irene; Dang, Minghao; Poteete, Alissa; Zhang, Fahao; Wang, Qi; Wang, Jing; Parra, Edwin Roger; Skoulidis, Ferdinandos; Wistuba, Ignacio I.; Verma, Svena; Merghoub, Taha; Wolchok, Jedd D.; Wong, Kwok-Kin; DeBerardinis, Ralph J.; Minna, John D.; Wang, Linghua; Reuben, Alexandre; Heymach, John V.

doi:10.2139/ssrn.4226205

Cited by 6 publications

(7 citation statements)

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“…In patients with high HERC5 expression, ISG15 and USP18 (ISG15 de-ubiquitinylase) were among the top 10 regulated proteins, which are the main interaction partners of HERC5 mediated ISGylation. In patients with low expression on the other hand, the most strongly regulated protein was SLC16A4, which has been recently described to be involved in alterations of glucose and lactate metabolism and metastasis also in NSCLC [41][42][43]. Overall, cell line and patient data indicate that in NSCLC the HERC5associated alterations in mitochondrial metabolism are independent of its ISGylation function.…”

Section: Herc5 Induces Changes In the Mitochondrial Protein Compositi...mentioning

confidence: 89%

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Schneegans,

Löptien,

Mojzisch

et al. 2024

J Exp Clin Cancer Res

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Background Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the “metastasis-suppressor” effect of HERC5, with a focus on mitochondrial metabolism pathways. Methods We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways. Results Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation. Conclusions Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.

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Section: Herc5 Induces Changes In the Mitochondrial Protein Compositi...mentioning

confidence: 89%

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Schneegans,

Löptien,

Mojzisch

et al. 2024

J Exp Clin Cancer Res

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“…Regulate cancer metabolism through effects on triosephosphate isomerase (TPI) or altered lactate production and secretion; 2. Regulate transcription effects on histone acetylation via elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs) or effects on HDAC1/3 or some other signaling circuit remains to be determined [57][58][59][60][61][62] .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ULK1/2 and KRAS^G12Ccontrols tumor growth in preclinical models of lung cancer

Ghazi,

O’Toole,

Srinivas Boggaram

et al. 2024

Preprint

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Mutational activation ofKRASoccurs commonly in lung carcinogenesis and, with the recent FDA approval of covalent inhibitors of KRASG12Csuch as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients that do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here we report that inhibition of KRASG12Csignaling increases autophagy in KRASG12Cexpressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRASG12C-driven lung cancer cell proliferationin vitroand superior tumor controlin vivo. Additionally, in genetically engineered mouse models of KRASG12C-driven NSCLC, inhibition of either KRASG12Cor ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRASG12Cin lung cancer.

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“…Glycolytic tumors increase the availability of lactate in the tumor microenvironment. 115–117 Lactate promotes PD-1 expression and limits IF-γ production in tumor-infiltrating regulatory T cells, promoting an immunosuppressive environment. 118 In macrophages, lactate promotes polarization and HIF1-α stabilization, 119 causing epigenetic modifications 120 and transcriptional activation of genes, including IL-6 and ARG1 (arginase 1).…”

Section: Effect Of Cancer-associated Inflammation On Cardiac Metaboli...mentioning

confidence: 99%

Intersection of Immunology and Metabolism in Myocardial Disease

Thorp,

Karlstaedt

2024

Circulation Research

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Immunometabolism is an emerging field at the intersection of immunology and metabolism. Immune cell activation plays a critical role in the pathogenesis of cardiovascular diseases and is integral for regeneration during cardiac injury. We currently possess a limited understanding of the processes governing metabolic interactions between immune cells and cardiomyocytes. The impact of this intercellular crosstalk can manifest as alterations to the steady state flux of metabolites and impact cardiac contractile function. Although much of our knowledge is derived from acute inflammatory response, recent work emphasizes heterogeneity and flexibility in metabolism between cardiomyocytes and immune cells during pathological states, including ischemic, cardiometabolic, and cancer-associated disease. Metabolic adaptation is crucial because it influences immune cell activation, cytokine release, and potential therapeutic vulnerabilities. This review describes current concepts about immunometabolic regulation in the heart, focusing on intercellular crosstalk and intrinsic factors driving cellular regulation. We discuss experimental approaches to measure the cardio-immunologic crosstalk, which are necessary to uncover unknown mechanisms underlying the immune and cardiac interface. Deeper insight into these axes holds promise for therapeutic strategies that optimize cardioimmunology crosstalk for cardiac health.

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MCT4-Dependent Lactate Secretion Suppresses Antitumor Immunity in LKB1-Deficient NSCLC

Cited by 6 publications

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HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Inhibition of ULK1/2 and KRAS^G12Ccontrols tumor growth in preclinical models of lung cancer

Intersection of Immunology and Metabolism in Myocardial Disease

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MCT4-Dependent Lactate Secretion Suppresses Antitumor Immunity in LKB1-Deficient NSCLC

Cited by 6 publications

References 0 publications

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis

Inhibition of ULK1/2 and KRASG12Ccontrols tumor growth in preclinical models of lung cancer

Intersection of Immunology and Metabolism in Myocardial Disease

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Inhibition of ULK1/2 and KRAS^G12Ccontrols tumor growth in preclinical models of lung cancer