bims-meluca 2021-06-27 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–06–27
eight papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge and Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.
The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer.
A novel Nrf2 pathway inhibitor sensitizes Keap1-mutant lung cancer cells to chemotherapy.
Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer.
Characteristics of hypoxic tumor microenvironment in non-small cell lung cancer, involving molecular patterns and prognostic signature.
Metabolic features of cancer cells impact immunosurveillance.
Glucagon regulates the stability of REV-ERBα to modulate hepatic glucose production in a model of lung cancer-associated cachexia.
PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs.

iScience. 2021 Jun 25. 24(6): 102649

KEAP1 deficiency drives glucose dependency and sensitizes lung cancer cells and tumors to GLUT inhibition.

Pranavi Koppula, Kellen Olszewski, Yilei Zhang, Lavanya Kondiparthi, Xiaoguang Liu, Guang Lei, Molina Das, Bingliang Fang, Masha V Poyurovsky, Boyi Gan.

  Metabolic reprogramming in cancer cells can create metabolic liabilities. KEAP1-mutant lung cancer is refractory to most current therapies. Here we show that KEAP1 deficiency promotes glucose dependency in lung cancer cells, and KEAP1-mutant/deficient lung cancer cells are more vulnerable to glucose deprivation than their WT counterparts. Mechanistically, KEAP1 inactivation in lung cancer cells induces constitutive activation of NRF2 transcription factor and aberrant expression of NRF2 target cystine transporter SLC7A11; under glucose limitation, high cystine uptake in KEAP1-inactivated lung cancer cells stimulates toxic intracellular disulfide buildup, NADPH depletion, and cell death, which can be rescued by genetic ablation of NRF2-SLC7A11 axis or treatments inhibiting disulfide accumulation. Finally, we show that KEAP1-inactivated lung cancer cells or xenograft tumors are sensitive to glucose transporter inhibitor. Together, our results reveal that KEAP1 deficiency induces glucose dependency in lung cancer cells and uncover a therapeutically relevant metabolic liability.

Keywords:  cancer; cell biology; physiology

DOI:  https://doi.org/10.1016/j.isci.2021.102649
Front Immunol. 2021 ;12 689132

The Combination of Immune Checkpoint Blockade and Angiogenesis Inhibitors in the Treatment of Advanced Non-Small Cell Lung Cancer.

Sijia Ren, Xinxin Xiong, Hua You, Jianfei Shen, Penghui Zhou.

  Immune checkpoint blockade (ICB) has become a standard treatment for non-small cell lung cancer (NSCLC). However, most patients with NSCLC do not benefit from these treatments. Abnormal vasculature is a hallmark of solid tumors and is involved in tumor immune escape. These abnormalities stem from the increase in the expression of pro-angiogenic factors, which is involved in the regulation of the function and migration of immune cells. Anti-angiogenic agents can normalize blood vessels, and thus transforming the tumor microenvironment from immunosuppressive to immune-supportive by increasing the infiltration and activation of immune cells. Therefore, the combination of immunotherapy with anti-angiogenesis is a promising strategy for cancer treatment. Here, we outline the current understanding of the mechanisms of vascular endothelial growth factor/vascular endothelial growth factor receptor (VEGF/VEGFR) signaling in tumor immune escape and progression, and summarize the preclinical studies and current clinical data of the combination of ICB and anti-angiogenic drugs in the treatment of advanced NSCLC.

Keywords:  NSCLC; angiogenesis inhibitors; combination therapy; immune checkpoint blockade; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2021.689132
Mol Cancer Ther. 2021 Jun 22. pii: molcanther.0210.2021. [Epub ahead of print]

A novel Nrf2 pathway inhibitor sensitizes Keap1-mutant lung cancer cells to chemotherapy.

Di Zhang, Zhilin Hou, Kelly E Aldrich, Lizbeth Lockwood, Aaron L Odom, Karen T Liby.

The Nrf2-Keap1-ARE pathway, a master regulator of oxidative stress, has emerged as a promising target for cancer therapy. Mutations in NFE2L2, KEAP1, and related genes have been found in many human cancers, especially lung cancer. These mutations lead to constitutive activation of the Nrf2 pathway, which promotes proliferation of cancer cells and their resistance to chemotherapies. Small molecules that inhibit the Nrf2 pathway are needed to arrest tumor growth and overcome chemoresistance in Nrf2 addicted cancers. Here, we identified a novel small molecule, MSU38225, which can suppress Nrf2 pathway activity. MSU38225 downregulates Nrf2 transcriptional activity and decreases the expression of Nrf2 downstream targets, including NQO1, GCLC, GCLM, AKR1C2 and UGT1A6. MSU38225 strikingly decreases the protein level of Nrf2, which can be blocked by the proteasome inhibitor MG132. Ubiquitination of Nrf2 is enhanced following treatment with MSU38225. By inhibiting production of antioxidants, MSU38225 increases the level of reactive oxygen species when cells are stimulated with tert-butyl hydroperoxide. MSU38225 also inhibits the growth of human lung cancer cells in both 2D cell culture and soft agar. Cancer cells addicted to Nrf2 are more susceptible to MSU38225 for suppression of cell proliferation. MSU38225 also sensitizes human lung cancer cells to chemotherapies both in vitro and in vivo. Our results suggest that MSU38225 is a novel Nrf2 pathway inhibitor that could potentially serve as an adjuvant therapy to enhance the response to chemotherapies in lung cancer patients.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0210
Front Oncol. 2021 ;11 647559

Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer.

Jun Jiang, DengLiang Huang, Yuan Jiang, Jing Hou, MeiYuan Tian, JianHua Li, Li Sun, YaoGang Zhang, Tao Zhang, ZhiQin Li, ZhongCheng Li, SiXian Tong, YanYan Ma.

  Lactate has been observed to fuel TCA cycle and is associated with cancer progression in human lung cancer, the leading cause of cancer deaths worldwide, but the effect of lactate on lung cancer metabolism is rarely reported. In this study, disordered metabolism in non-small cell lung cancer was demonstrated by increased G6PD and SDHA protein levels via immunofluorescence, and up-regulated lactate dehydrogenase was found to be associated with poor prognosis. Then flow cytometry and Seahorse XFe analyzer were utilized to detect the effect of lactate on glycolysis and mitochondrial function in non-small cell lung cancer cells. The results show that in non-small cell lung cancer cells lactate attenuates glucose uptake and glycolysis while maintaining mitochondrial homeostasis as indicated by improved mitochondrial membrane potential. Further exploration found that mRNA levels of glycolytic enzymes (HK-1, PKM) and TCA cycle enzymes (SDHA, IDH3G) are respectively down-regulated and up-regulated by lactate, and increased histone lactylation was observed in promoters of HK-1 and IDH3G via chromatin immunoprecipitation assay. Taken together, the above results indicate that lactate modulates cellular metabolism at least in part through histone lactylation-mediated gene expression in non-small cell lung cancer.

Keywords:  gene expression; lactate; lactylation; metabolism; non-small cell lung cancer

DOI:  https://doi.org/10.3389/fonc.2021.647559
Transl Lung Cancer Res. 2021 May;10(5): 2132-2147

Characteristics of hypoxic tumor microenvironment in non-small cell lung cancer, involving molecular patterns and prognostic signature.

Zhanghao Huang, Shuo Wang, Hai-Jian Zhang, You Lang Zhou, Xin Tang, Jia-Hai Shi.

   Background: The mechanisms of hypoxia or immune microenvironment in cancer have been studied respectively, but the role of hypoxia immune microenvironment in non-small cell lung cancer (NSCLC) still needs further exploration.
Methods: By applying the K-means algorithm, 1,121 patients with NSCLC were divided into three categories. We evaluated the constructed signature in order to link it with the prognosis, which was constructed by univariate and least absolute shrinkage operator (LASSO) Cox regression analysis.
Results: A total of three clusters were obtained by clustering five Gene Expression Omnibus (GEO) data sets. Gene Set Variation Analysis (GSVA) and immune infiltration analysis were performed to explore the biological behavior. Cluster one presented an activated state of oncogenic pathways, and compared with the other two clusters, the median risk score was the highest, which was the reason for its poor survival. Cluster three showed that the immune pathway was active and the median risk score was the lowest, so the survival was the best. However, cluster two presented a state in which both immune and matrix pathways were activate. This was manifested as mutual antagonism, and its risk score was in the middle. Its survival was in the middle.
Conclusions: This work revealed the role of hypoxia related genes (HRGs) modification in tumor microenvironment, which was conducive to our comprehensive analysis of the prognosis of NSCLC, and provided direction and guidance for clinical immunotherapy.

Keywords:  Gene Set Variation Analysis (GSVA); Hypoxia related genes (HRGs); immune infiltration; prognosis

DOI:  https://doi.org/10.21037/tlcr-20-1314
J Immunother Cancer. 2021 Jun;pii: e002362. [Epub ahead of print]9(6):

Metabolic features of cancer cells impact immunosurveillance.

Adrien Joseph, Pan Juncheng, Michele Mondini, Nizar Labaied, Mauro Loi, Julien Adam, Antoine Lafarge, Valentina Astesana, Florine Obrist, Christophe Klein, Norma Bloy, Gautier Stoll, Nicolas Signolle, Catherine Genestie, Diane Damotte, Marco Alifano, Alexandra Leary, Patricia Pautier, Philippe Morice, Sebastien Gouy, Eric Deutsch, Cyrus Chargari, Marie-Caroline Dieu-Nosjean, Isabelle Cremer, Judith Michels, Guido Kroemer, Maria Castedo.

   BACKGROUND: Tumors rewire their metabolism to achieve robust anabolism and resistance against therapeutic interventions like cisplatin treatment. For example, a prolonged exposure to cisplatin causes downregulation of pyridoxal kinase (PDXK), the enzyme that generates the active vitamin B6, and upregulation of poly ADP-ribose (PAR) polymerase-1 (PARP1) activity that requires a supply of nicotinamide (vitamin B3) adenine dinucleotide. We investigated the impact of the levels of PDXK and PAR on the local immunosurveillance (ie, density of the antigen presenting cells and adaptive immune response by CD8 T lymphocytes) in two different tumor types.
METHODS: Tumors from patients with locally advanced cervical carcinoma (LACC) and non-small cell lung cancer (NSCLC) were stained for PAR, PDXK, dendritic cell lysosomal associated membrane glycoprotein (DC-LAMP) and CD8 T cell infiltration. Their correlations and prognostic impact were assessed. Cisplatin-resistant NSCLC cell clones isolated from Lewis-lung cancer (LLC) cells were evaluated for PAR levels by immunoblot. Parental (PARlow) and cisplatin-resistant (PARhigh) clones were subcutaneously injected into the flank of C57BL/6 mice. Tumors were harvested to evaluate their immune infiltration by flow cytometry.
RESULTS: The infiltration of tumors by CD8 T and DC-LAMP+ cells was associated with a favorable overall survival in patients with LACC (p=0.006 and p=0.008, respectively) and NSCLC (p<0.001 for both CD8 T and DC-LAMP cells). We observed a positive correlation between PDXK expression and the infiltration by DC-LAMP (R=0.44, p=0.02 in LACC, R=0.14, p=0.057 in NSCLC), and a negative correlation between PAR levels and CD8 T lymphocytes (R=-0.39, p=0.034 in LACC, R=-0.18, p=0.017 in NSCLC). PARP1 is constitutively hyperactivated in cisplatin-resistant LLC cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PARhigh). Tumors formed by such cancer cells injected into immunocompetent mice were scarcely infiltrated by CD8 T (p=0.028) and antigen presenting cells (p=0.086).
CONCLUSIONS: Oncometabolic features can impact local immunosurveillance, providing new functional links between cisplatin resistance and therapeutic failure.

Keywords:  CD8-positive t-lymphocytes; dendritic cells; immunotherapy; lung neoplasms; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2021-002362
Sci Adv. 2021 Jun;pii: eabf3885. [Epub ahead of print]7(26):

Glucagon regulates the stability of REV-ERBα to modulate hepatic glucose production in a model of lung cancer-associated cachexia.

Amandine Verlande, Sung Kook Chun, Maggie O Goodson, Bridget M Fortin, Hosung Bae, Cholsoon Jang, Selma Masri.

Lung adenocarcinoma is associated with cachexia, which manifests as an inflammatory response that causes wasting of adipose tissue and skeletal muscle. We previously reported that lung tumor-bearing (TB) mice exhibit alterations in inflammatory and hormonal signaling that deregulate circadian pathways governing glucose and lipid metabolism in the liver. Here, we define the molecular mechanism of how de novo glucose production in the liver is enhanced in a model of lung adenocarcinoma. We found that elevation of serum glucagon levels stimulates cyclic adenosine monophosphate production and activates hepatic protein kinase A (PKA) signaling in TB mice. In turn, we found that PKA targets and destabilizes the circadian protein REV-ERBα, a negative transcriptional regulator of gluconeogenic genes, resulting in heightened de novo glucose production. Together, we identified that glucagon-activated PKA signaling regulates REV-ERBα stability to control hepatic glucose production in a model of lung cancer-associated cachexia.

DOI: https://doi.org/10.1126/sciadv.abf3885
Oncogene. 2021 Jun 21.

PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs.

Chia-Hung Chen, Bo-Wei Wang, Yu-Chun Hsiao, Chun-Yi Wu, Fang-Ju Cheng, Te-Chun Hsia, Chih-Yi Chen, Yihua Wang, Zhang Weihua, Ruey-Hwang Chou, Chih-Hsin Tang, Yun-Ju Chen, Ya-Ling Wei, Jennifer L Hsu, Chih-Yen Tu, Mien-Chie Hung, Wei-Chien Huang.

The tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have been widely used for non-small cell lung cancer (NSCLC) patients, but the development of acquired resistance remains a therapeutic hurdle. The reduction of glucose uptake has been implicated in the anti-tumor activity of EGFR TKIs. In this study, the upregulation of the active sodium/glucose co-transporter 1 (SGLT1) was found to confer the development of acquired EGFR TKI resistance and was correlated with the poorer clinical outcome of the NSCLC patients who received EGFR TKI treatment. Blockade of SGLT1 overcame this resistance in vitro and in vivo by reducing glucose uptake in NSCLC cells. Mechanistically, SGLT1 protein was stabilized through the interaction with PKCδ-phosphorylated (Thr678) EGFR in the TKI-resistant cells. Our findings revealed that PKCδ/EGFR axis-dependent SGLT1 upregulation was a critical mechanism underlying the acquired resistance to EGFR TKIs. We suggest co-targeting PKCδ/SGLT1 as a potential strategy to improve the therapeutic efficacy of EGFR TKIs in NSCLC patients.

DOI: https://doi.org/10.1038/s41388-021-01889-0