bims-meluca 2021-12-26 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2021–12–26
seven 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

Protein modifications throughout the lung cancer proteome unravel the cancer-specific regulation of glycolysis.
HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer.
Impact of Sarcopenia and Inflammation on Patients with Advanced Non-Small Cell Lung Cancer (NCSCL) Treated with Immune Checkpoint Inhibitors (ICIs): A Prospective Study.
Lung Adenocarcinoma Transcriptomic Analysis Predicts Adenylate Kinase Signatures Contributing to Tumor Progression and Negative Patient Prognosis.
Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities.
Prognostic Implications and Immune Infiltration Analysis of ALDOA in Lung Adenocarcinoma.
p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer.

Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01633-8. [Epub ahead of print]37(12): 110137

Protein modifications throughout the lung cancer proteome unravel the cancer-specific regulation of glycolysis.

Yangmiao Duan, Jingyi Li, Fengqin Wang, Junmin Wei, Zhongfa Yang, Mingxin Sun, Jia Liu, Mingxin Wen, Wan Huang, Zhinan Chen, Zhimin Lu, Jing-Hua Yang, Guangwei Wei.

  Glycolytic reprogramming is a typical feature of cancer. However, the cancer-specific modulation of glycolytic enzymes requires systematic elucidation. Here, we report a range of dysregulated modifications in association with a family of enzymes specifically related to the glycolysis pathway by systematic identification of delta masses at the proteomic scale in human non-small-cell lung cancer. The most significant modification is the delta mass of 79.967 Da at serine 58 (Ser58) of triosephosphate isomerase (TPI), which is confirmed to be phosphorylation. Blocking TPI Ser58 phosphorylation dramatically inhibits glycolysis, cancer growth, and metastasis. The protein kinase PRKACA directly phosphorylates TPI Ser58, thereby enhancing TPI enzymatic activity and glycolysis. The upregulation of TPI Ser58 phosphorylation is detected in various human tumor specimens and correlates with poor survival. Therefore, our study identifies a number of cancer-specific protein modifications spanned on glycolytic enzymes and unravels the significance of TPI Ser58 phosphorylation in glycolysis and lung cancer development.

Keywords:  Post-translational modification; aerobic glycolysis; lung cancer; phosphorylation; triosephosphate isomerase

DOI:  https://doi.org/10.1016/j.celrep.2021.110137
J Exp Clin Cancer Res. 2021 Dec 20. 40(1): 398

HIF-1α switches the functionality of TGF-β signaling via changing the partners of smads to drive glucose metabolic reprogramming in non-small cell lung cancer.

Yiwei Huang, Zhencong Chen, Tao Lu, Guoshu Bi, Ming Li, Jiaqi Liang, Zhengyang Hu, Yuansheng Zheng, Jiacheng Yin, Junjie Xi, Zongwu Lin, Cheng Zhan, Wei Jiang, Qun Wang, Lijie Tan.

   BACKGROUND: Most cancer cells have fundamentally different metabolic characteristics, particularly much higher glycolysis rates than normal tissues, which support the increased demand for biosynthesis and promote tumor progression. We found that transforming growth factor (TGF)-β plays a dual function in regulating glycolysis and cell proliferation in non-small cell lung cancer.
METHODS: We used the PET/MRI imaging system to observe the glucose metabolism of subcutaneous tumors in nude mice. Energy metabolism of non-small cell lung cancer cell lines detected by the Seahorse XFe96 cell outflow analyzer. Co-immunoprecipitation assays were used to detect the binding of Smads and HIF-1α. Western blotting and qRT-PCR were used to detect the regulatory effects of TGF-β and HIF-1α on c-MYC, PKM1/2, and cell cycle-related genes.
RESULTS: We discovered that TGF-β could inhibit glycolysis under normoxia while significantly promoting tumor cells' glycolysis under hypoxia in vitro and in vivo. The binding of hypoxia-inducible factor (HIF)-1α to the MH2 domain of phosphorylated Smad3 switched TGF-β function to glycolysis by changing Smad partners under hypoxia. The Smad-p107-E2F4/5 complex that initially inhibited c-Myc expression was transformed into a Smad-HIF-1α complex that promoted the expression of c-Myc. The increased expression of c-Myc promoted alternative splicing of PKM to PKM2, resulting in the metabolic reprogramming of tumor cells. In addition, the TGF-β/Smad signal lost its effect on cell cycle regulatory protein p15/p21. Furthermore, high expression of c-Myc inhibited p15/p21 and promoted the proliferation of tumor cells under hypoxia.
CONCLUSIONS: Our results indicated that HIF-1α functions as a critical factor in the dual role of TGF-β in tumor cells, and may be used as a biomarker or therapeutic target for TGF-β mediated cancer progression.

Keywords:  Cell cycle; HIF-1α; Metabolic reprogramming; TGF-β/Smad signaling pathway

DOI:  https://doi.org/10.1186/s13046-021-02188-y
Cancers (Basel). 2021 Dec 17. pii: 6355. [Epub ahead of print]13(24):

Impact of Sarcopenia and Inflammation on Patients with Advanced Non-Small Cell Lung Cancer (NCSCL) Treated with Immune Checkpoint Inhibitors (ICIs): A Prospective Study.

Marta Tenuta, Alain Gelibter, Carla Pandozzi, Grazia Sirgiovanni, Federica Campolo, Mary Anna Venneri, Salvatore Caponnetto, Enrico Cortesi, Paolo Marchetti, Andrea M Isidori, Emilia Sbardella.

   BACKGROUND: Sarcopenia is a condition characterized by loss of skeletal muscle mass associated with worse clinical outcomes in cancer patients. Data on sarcopenia in patients undergoing immune checkpoint inhibitors (ICI) therapy are still limited. The aim of this prospective observational study was to investigate the relationship between sarcopenia, ICI treatment response and immunological profile, in patients with advanced non-small cell lung cancer (NSCLC).
METHODS: Forty-seven stage IV NSCLC patient candidates for starting ICI, were enrolled from the Policlinico Umberto I outpatient Oncology. Patients underwent baseline blood test, inflammatory markers, cytokine assessment and body composition with dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined with appendicular skeletal muscle mass over height2 (ASM/heigh2).
RESULTS: Overall, 19/47 patients (40.4%) results were sarcopenic. Sarcopenic patients showed significantly shorter PFS than non-sarcopenic ones (20.3 weeks, 95% CI 7.5-33.1 vs. 61 weeks, 95% CI 22.5-99.4, p = 0.047). Specifically, they had an 8.1 times higher risk of progression disease (PD) than non-sarcopenic patients (OR 8.1, 95%, p = 0.011).
CONCLUSIONS: Sarcopenic patients showed worse PFS and had a higher risk of PD compared to non-sarcopenic ones. Therefore, sarcopenia may reflect the increased metabolic activity of more aggressive tumors, which involves systemic inflammation and muscle wasting and could be considered a negative predictive factor for ICI response.

Keywords:  PDL1; biomarker; immunotherapy; lung cancer; sarcopenia

DOI:  https://doi.org/10.3390/cancers13246355
Metabolites. 2021 Dec 09. pii: 859. [Epub ahead of print]11(12):

Lung Adenocarcinoma Transcriptomic Analysis Predicts Adenylate Kinase Signatures Contributing to Tumor Progression and Negative Patient Prognosis.

Jonathan A Chacon-Barahona, Ivan A Salladay-Perez, Nathan James Lanning.

  The ability to detect and respond to hypoxia within a developing tumor appears to be a common feature amongst most cancers. This hypoxic response has many molecular drivers, but none as widely studied as Hypoxia-Inducible Factor 1 (HIF-1). Recent evidence suggests that HIF-1 biology within lung adenocarcinoma (LUAD) may be associated with expression levels of adenylate kinases (AKs). Using LUAD patient transcriptome data, we sought to characterize AK gene signatures related to lung cancer hallmarks, such as hypoxia and metabolic reprogramming, to identify conserved biological themes across LUAD tumor progression. Transcriptomic analysis revealed perturbation of HIF-1 targets to correlate with altered expression of most AKs, with AK4 having the strongest correlation. Enrichment analysis of LUAD tumor AK4 gene signatures predicts signatures involved in pyrimidine, and by extension, nucleotide metabolism across all LUAD tumor stages. To further discriminate potential drivers of LUAD tumor progression within AK4 gene signatures, partial least squares discriminant analysis was used at LUAD stage-stage interfaces, identifying candidate genes that may promote LUAD tumor growth or regression. Collectively, these results characterize regulatory gene networks associated with the expression of all nine human AKs that may contribute to underlying metabolic perturbations within LUAD and reveal potential mechanistic insight into the complementary role of AK4 in LUAD tumor development.

Keywords:  HIF-1; adenylate kinase; hypoxia; lung cancer; tumor progression

DOI:  https://doi.org/10.3390/metabo11120859
Front Oncol. 2021 ;11 792827

Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities.

Peyman Tabnak, Zanyar HajiEsmailPoor, Soroush Soraneh.

  Lung cancer is the second commonly diagnosed malignancy worldwide and has the highest mortality rate among all cancers. Tremendous efforts have been made to develop novel strategies against lung cancer; however, the overall survival of patients still is low. Uncovering underlying molecular mechanisms of this disease can open up new horizons for its treatment. Ferroptosis is a newly discovered type of programmed cell death that, in an iron-dependent manner, peroxidizes unsaturated phospholipids and results in the accumulation of radical oxygen species. Subsequent oxidative damage caused by ferroptosis contributes to cell death in tumor cells. Therefore, understanding its molecular mechanisms in lung cancer appears as a promising strategy to induce ferroptosis selectively. According to evidence published up to now, significant numbers of research have been done to identify ferroptosis regulators in lung cancer. Therefore, this review aims to provide a comprehensive standpoint of molecular mechanisms of ferroptosis in lung cancer and address these molecules' prognostic and therapeutic values, hoping that the road for future studies in this field will be paved more efficiently.

Keywords:  Nrf2; ROS; biomarkers; cell death; ferroptosis; immunity; iron metabolism; lung cancer

DOI:  https://doi.org/10.3389/fonc.2021.792827
Front Genet. 2021 ;12 721021

Prognostic Implications and Immune Infiltration Analysis of ALDOA in Lung Adenocarcinoma.

Guojun Lu, Wen Shi, Yu Zhang.

  Background: aldolase A (ALDOA) has been reported to be involved in kinds of cancers. However, the role of ALDOA in lung adenocarcinoma has not been fully elucidated. In this study, we explored the prognostic value and correlation with immune infiltration of ALDOA in lung adenocarcinoma. Methods: The expression of ALDOA was analyzed with the Oncomine database, the Cancer Genome Atlas (TCGA), and the Human Protein Atlas (HPA). Mann-Whitney U test was performed to examine the relationship between clinicopathological characteristics and ALDOA expression. The receiver operating characteristic (ROC) curve and Kaplan-Meier method were conducted to describe the diagnostic and prognostic importance of ALDOA. The Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape were used to construct PPI networks and identify hub genes. Functional annotations and immune infiltration were conducted. Results: The mRNA and protein expression of ALDOA were higher in lung adenocarcinoma than those in normal tissues. The overexpression of ALDOA was significantly correlated with the high T stage, N stage, M stage, and TNM stage. Kaplan-Meier showed that high expression of ALDOA was correlated with short overall survival (38.9 vs 72.5 months, p < 0.001). Multivariate analysis revealed that ALDOA (HR 1.435, 95%CI, 1.013-2.032, p = 0.042) was an independent poor prognostic factor for overall survival. Functional enrichment analysis showed that positively co-expressed genes of ALDOA were involved in the biological progress of mitochondrial translation, mitochondrial translational elongation, and negative regulation of cell cycle progression. KEGG pathway analysis showed enrichment function in carbon metabolism, the HIF-1 signaling pathway, and glycolysis/gluconeogenesis. The "SCNA" module analysis indicated that the copy number alterations of ALDOA were correlated with three immune cell infiltration levels, including B cells, CD8+ T cells, and CD4+ T cells. The "Gene" module analysis indicated that ALDOA gene expression was negatively correlated with infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, and macrophages. Conclusion: Our study suggested that upregulated ALDOA was significantly correlated with tumor progression, poor survival, and immune infiltrations in lung adenocarcinoma. These results suggest that ALDOA is a potential prognostic biomarker and therapeutic target in lung adenocarcinoma.

Keywords:  AldoA; biomarker; immune infiltration; lung adenocarcinoma; prognosis

DOI:  https://doi.org/10.3389/fgene.2021.721021
Cells. 2021 Nov 30. pii: 3363. [Epub ahead of print]10(12):

p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer.

Izabela Zarczynska, Monika Gorska-Arcisz, Alexander Jorge Cortez, Katarzyna Aleksandra Kujawa, Agata Małgorzata Wilk, Andrzej Cezary Skladanowski, Aleksandra Stanczak, Monika Skupinska, Maciej Wieczorek, Katarzyna Marta Lisowska, Rafal Sadej, Kamila Kitowska.

  FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.

Keywords:  FGFR; acquired resistance; lung cancer; p38

DOI:  https://doi.org/10.3390/cells10123363