bims-meluca 2024-01-07 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–01–07
ten papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.
Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy.
Clinical significance of antinuclear antibody as prognostic marker for first-line pembrolizumab in advanced non-small cell lung cancer.
PLA2G2D fosters angiogenesis in non-small cell lung cancer through aerobic glycolysis.
IL-17A as a new circulating bioindicator for non-small cell lung cancer diagnosis and prognosis.
Short-term effects of preoperative nutritional intervention in lung surgery for malignant tumors: a single-center prospective study.
Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.
Lipidomics reveals immune-related adverse events in NSCLC patients receiving immune checkpoint inhibitor.
Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma.
Clinical and Genomic Characterization of Long-Term Responders Receiving Immune Checkpoint Blockade for Metastatic Non-Small-Cell Lung Cancer.

Cell Rep. 2023 Dec 30. pii: S2211-1247(23)01640-6. [Epub ahead of print]43(1): 113629

Metabolic reprogramming by histone deacetylase inhibition preferentially targets NRF2-activated tumors.

Dimitris Karagiannis, Warren Wu, Albert Li, Makiko Hayashi, Xiao Chen, Michaela Yip, Vaibhav Mangipudy, Xinjing Xu, Francisco J Sánchez-Rivera, Yadira M Soto-Feliciano, Jiangbin Ye, Thales Papagiannakopoulos, Chao Lu.

  The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.

Keywords:  CP: Cancer; HDAC inhibitors; NRF2 pathway; cancer epigenetics; cancer metabolism; cancer targeted therapy; epigenetic reprogramming; lung cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.113629
J Exp Clin Cancer Res. 2024 Jan 02. 43(1): 6

Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy.

Gloriana Ndembe, Ilenia Intini, Massimo Moro, Chiara Grasselli, Andrea Panfili, Nicolò Panini, Augusto Bleve, Mario Occhipinti, Cristina Borzi, Marina Chiara Garassino, Mirko Marabese, Simone Canesi, Eugenio Scanziani, Gabriella Sozzi, Massimo Broggini, Monica Ganzinelli.

   BACKGROUND: About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRASmut/LKB1mut patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors.
METHODS: Mouse cell lines were derived from lung nodules of transgenic mice carrying KRASG12D with either functional LKB1 (KRASG12D/LKB1wt) or mutated LKB1 (KRASG12D/LKB1mut). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice. The mice bearing these tumor models were subjected to treatment with chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR.
RESULTS: Our preclinical results indicate that in NSCLC KRASmut/LKB1mut tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR.
CONCLUSION: Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.

Keywords:  Caloric restriction; Cancer metabolism; KRAS; LKB1; Metformin; NSCLC

DOI:  https://doi.org/10.1186/s13046-023-02933-5
Int J Clin Oncol. 2023 Dec 31.

Clinical significance of antinuclear antibody as prognostic marker for first-line pembrolizumab in advanced non-small cell lung cancer.

Atsuto Mouri, Kyoichi Kaira, Ou Yamaguchi, Kosuke Hashimoto, Yu Miura, Ayako Shiono, Tomonori Kawasaki, Kunihiko Kobayashi, Hisao Imai, Hiroshi Kagamu.

   BACKGROUND: The relationship between antinuclear antibody (ANA) and the efficacy of programmed death-1 (PD-1) blockade remains controversial. Here, we investigated the prognostic significance of ANA titer in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab monotherapy as the first-line treatment, compared with that of platinum-based chemotherapy with PD-1 blockade.
METHODS: Our clinical data based on the ANA titer (1:80) were retrospectively reviewed for patients with advanced NSCLC, who were treated with first-line pembrolizumab monotherapy and platinum-based chemotherapy with PD-1 blockade. Immunohistochemical staining for tumor-infiltrating lymphocytes such as CD4, CD8 and Foxp3 was performed.
RESULTS: Among 106 patients treated with pembrolizumab, 19 (17.9%) tested high for ANA. Progression-free survival (PFS) and overall survival (OS) were significantly better in patients with high ANA than in those with low ANA, and high ANA was identified as an independent prognostic predictor, particularly in the subgroup with programmed death ligand-1 (PD-L1) ≥ 50%. However, no statistically significant difference in PFS and OS based on the ANA titer was observed in 59 patients treated with combinational chemotherapy and immunotherapy. High numbers of intratumoral Foxp3 and stromal CD8 were significantly associated with low ANA.
CONCLUSIONS: Assessment of preexisting ANA titers was useful to prognose PD-1 blockade as a first-line setting, particularly for the PD-L1 ≥ 50% subgroup, but not in the case of combined immunotherapy and chemotherapy.

Keywords:  Antinuclear antibody; Non-small cell lung cancer; PD-L1; Pembrolizumab

DOI:  https://doi.org/10.1007/s10147-023-02445-4
Growth Factors. 2024 Jan 01. 1-10

PLA2G2D fosters angiogenesis in non-small cell lung cancer through aerobic glycolysis.

Huaizhong Zhang, Keng Chen, Yongqing Zhou, Zhuo Cao, Cunlai Xu, Lin Zhou, Gongzhi Wu, Congxiong Peng, Songqing Lai, Xuhui Wu.

  Non-small cell lung cancer (NSCLC) stands prominent among the prevailing and formidable oncological entities. The immune and metabolic-related molecule Phospholipase A2, group IID (PLA2G2D) exerts promotional effects on tumor progression. However, its involvement in cancer angiogenesis remains elusive. Therefore, this investigation delved into the functional significance of PLA2G2D concerning angiogenesis in NSCLC. This study analyzed the expression and enriched pathways of PLA2G2D in NSCLC tissues through bioinformatics analysis, and measured the expression of PLA2G2D in NSCLC cells using qRT-PCR and western blot (WB). Subsequently, the viability and angiogenic potential of NSCLC cells were assessed employing CCK-8 and angiogenesis assays, respectively. The expression profile of angiogenic factors was analyzed through WB. Finally, the expression of glycolysis pathway-related genes, extracellular acidification rate and oxygen consumption rate, and the levels of pyruvate, lactate, citrate, and malate were analyzed in NSCLC cells using qRT-PCR, Seahorse XF 96, and related kits. Bioinformatics analysis revealed the upregulation of PLA2G2D in NSCLC tissues and its association with VEGF and glycolysis signaling pathways. Molecular and cellular experiments demonstrated that upregulated PLA2G2D promoted the viability, angiogenic ability, and glycolysis pathway of NSCLC cells. Rescue assays revealed that the effects of high expression of PLA2G2D on the viability, angiogenic ability, and glycolysis of NSCLC cells were weakened after the addition of the glycolysis inhibitor 2-DG. In summary, PLA2G2D plays a key role in NSCLC angiogenesis through aerobic glycolysis, displaying great potential as a target for anti-angiogenesis therapy.

Keywords:  NSCLC; PLA2G2D; angiogenesis; glycolysis

DOI:  https://doi.org/10.1080/08977194.2023.2297702
Eur Rev Med Pharmacol Sci. 2023 Dec;pii: 34798. [Epub ahead of print]27(24): 12004-12011

IL-17A as a new circulating bioindicator for non-small cell lung cancer diagnosis and prognosis.

J-X Wang, X-J Xu, Z-M Zhu, W-L Cao, Z-P Yang, J-L Zhen, Y-Y Wu, F-M Lu, S-W Liu.

OBJECTIVE: Lung cancer (LC) is the highest contributor to cancer-associated mortality worldwide. Approximately 85% of all LC incidences involve non-small cell LC (NSCLC). Unfortunately, owing to a significant lack of sensitive and robust bioindicators, most patient diagnoses occur at advanced stages of the disease, thereby resulting in extremely poor patient outcomes. Herein, we elucidated the role of interleukin-17A (IL-17A) among NSCLC patients.
MATERIALS AND METHODS: Circulating IL-17A content was measured using enzyme-linked immunosorbent assay (ELISA), and its diagnostic and prognostic abilities were assessed using the receiver operating characteristic (ROC) curve and Kaplan-Meier analysis, respectively.
RESULTS: Our analysis revealed that circulating IL-17A levels were significantly augmented among NSCLC vs. control samples. Moreover, based on our area under the curve (AUC) analysis, circulating IL-17A levels fared considerably better than the standard bioindicator carcinoembryonic antigen (CEA) in both testing and validation cohorts. Notably, we also revealed that the circulating IL-17A levels were accurately and reliably predicted in early-stage NSCLC patients. Besides, we demonstrated a strong correlation between elevated circulating IL-17A expression and worse prognosis among NSCLC patients.
CONCLUSIONS: Herein, we demonstrated that circulating IL-17A levels can serve as reliable and potent diagnostic and prognostic bioindicators for NSCLC.

DOI: https://doi.org/10.26355/eurrev_202312_34798
Gen Thorac Cardiovasc Surg. 2024 Jan 02.

Short-term effects of preoperative nutritional intervention in lung surgery for malignant tumors: a single-center prospective study.

Mamoru Takahashi, Harutaro Okada, Mako Kogaki, Rio Shirokihara, Yuka Kawate, Hironobu Tokumasu, Akihiro Aoyama.

   OBJECTIVES: Preoperative malnutrition is a risk factor for postoperative morbidity and mortality in patients with lung cancer. Assessing the preoperative nutritional status should be considered essential for patients scheduled to undergo lung surgery. This prospective study aimed to investigate whether preoperative nutritional intervention improves the nutritional conditions and short-term postoperative outcomes.
METHODS: The primary endpoints included safety, feasibility and short-term therapeutic efficacy of preoperative nutritional intervention. Patients with clinical stage I-III non-small cell lung cancer (histologically proven or suspected) were screened. Patient enrollment was conducted between January 2021 and December 2022. A total of 15 patients were included in the analysis. Patients with a preoperative prognostic nutritional index of < 45 were considered eligible. All participants received preoperative nutritional intervention. The trajectories of prognostic nutritional index and the incidence of postoperative complication rates in the intervention group were investigated.
RESULTS: No adverse events were observed during the nutritional intervention. The pre-intervention and post-intervention prognostic nutritional indices were 42.2 (39.8-44.5), and 43.1 (41.4-45.9), respectively (p = 0.04). The postoperative complication rate was 26.7% (n = 15).
CONCLUSIONS: This is the first prospective study to report the preoperative trajectories of prognostic nutritional index in patients undergoing lung cancer surgery. Our results suggest the safety and feasibility of preoperative nutritional intervention. Further research, such as randomized clinical trials, is warranted to investigate clinical efficacy and optimal nutritional interventions for lung surgery for malignant tumors.

Keywords:  Non-small cell lung cancer; Preoperative nutritional intervention; Prognostic nutritional index; Prospective study

DOI:  https://doi.org/10.1007/s11748-023-01998-5
Br J Cancer. 2023 Dec 30.

Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer.

Anaís Sánchez-Castillo, Elien Heylen, Judith Hounjet, Kim G Savelkouls, Natasja G Lieuwes, Rianne Biemans, Ludwig J Dubois, Kobe Reynders, Kasper M Rouschop, Rianne D W Vaes, Kim De Keersmaecker, Maarten Lambrecht, Lizza E L Hendriks, Dirk K M De Ruysscher, Marc Vooijs, Kim R Kampen.

BACKGROUND: Lung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy.
METHODS: We analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient's plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures.
RESULTS: Serine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels.
CONCLUSION: Our findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.

DOI: https://doi.org/10.1038/s41416-023-02553-y
Int Immunopharmacol. 2023 Dec 29. pii: S1567-5769(23)01739-3. [Epub ahead of print]127 111412

Lipidomics reveals immune-related adverse events in NSCLC patients receiving immune checkpoint inhibitor.

Jia Yu, Fen Xiong, Yingruo Xu, Hanyan Xu, Xi Zhang, Hongchang Gao, Yuping Li.

  There is a lack of reliable biomarkers to predict and identify the risk of immune-related adverse events (irAEs) in non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor (ICI) treatment. This study aims to explore potential biomarkers using lipidomics to identify and predict the risk of irAEs in NSCLC patients receiving ICI treatment. This prospective study enrolled 94 NSCLC patients with IIIB/IV stage NSCLC who underwent first-line chemotherapy in combination with ICI treatment. The prediction cohort consisted of plasma samples collected from 60 patients before ICI treatment, and the occurrence of irAE was monitored within 6 months of initiating first-line ICI therapy. The validation cohort comprised 34 patients, with plasma samples obtained from 15 patients who did not develop irAE at 6 months of ICI treatment and plasma samples collected from 19 irAE patients at the onset of irAE. Through non-targeted lipidomics and semi-targeted lipid quantification analysis, we identify 11 differentially metabolized lipids and further screened these lipids with the area under the curve (AUC) > 0.7 to predict the occurrence of irAEs in NSCLC patients following ICI treatment. The results showed that the biomarker panel consisting of 9 lipids (LPC-18:2, PC-40:6, LPC-22:6, LPC-O-18:0, PS-38:0, PC-38:6, PC-37:6, PC-36:5,LPC-17:0) exhibited a good AUC of 0.859 in the prediction and 0.940 in the validation cohort phase of the receiver operating characteristic curve; The study utilizes plasma lipidomics to develop a rapid and effective prediction model for identifying irAEs in advanced NSCLC patients who treatment with first-line chemotherapy combined with immunotherapy.

Keywords:  Biomarkers; Immune checkpoint inhibitors (ICIs); Immune-related adverse events (irAEs); Lipidomic; Lung cancer

DOI:  https://doi.org/10.1016/j.intimp.2023.111412
BMC Med Genomics. 2024 Jan 02. 17(1): 12

Integrated multi-omic analysis and experiment reveals the role of endoplasmic reticulum stress in lung adenocarcinoma.

Ying Liu, Wei Lin, Hongyan Qian, Ying Yang, Xuan Zhou, Chen Wu, Xiaoxia Pan, Yuan Liu, Gaoren Wang.

   BACKGROUND: Lung cancer is a highly prevalent malignancy worldwide and is associated with high mortality rates. While the involvement of endoplasmic reticulum (ER) stress in the development of lung adenocarcinoma (LUAD) has been established, the underlying mechanism remains unclear.
METHODS: In this study, we utilized data from The Cancer Genome Atlas (TCGA) to identify differentially expressed endoplasmic reticulum stress-related genes (ERSRGs) between LUAD and normal tissues. We performed various bioinformatics analyses to investigate the biological functions of these ERSRGs. Using LASSO analysis and multivariate stepwise regression, we constructed a novel prognostic model based on the ERSRGs. We further validated the performance of the model using two independent datasets from the Gene Expression Omnibus (GEO). Additionally, we conducted functional enrichment analysis, immune checkpoint analysis, and immune infiltration analysis and drug sensitivity analysis of LUAD patients to explore the potential biological function of the model. Furthermore, we conducted a battery of experiments to verify the expression of ERSRGs in a real-world cohort.
RESULTS: We identified 106 ERSRGs associated with LUAD, which allowed us to classify LUAD patients into two subtypes based on gene expression differences. Using six prognostic genes (NUPR1, RHBDD2, VCP, BAK1, EIF2AK3, MBTPS2), we constructed a prognostic model that exhibited excellent predictive performance in the training dataset and was successfully validated in two independent external datasets. The risk score derived from this model emerged as an independent prognostic factor for LUAD. Confirmation of the linkage between this risk model and immune infiltration was affirmed through the utilization of Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The q-PCR results verified significant differences in the expression of prognostic genes between cancer and paracancer tissues. Notably, the protein expression of NUPR1, as determined by immunohistochemistry (IHC), exhibited an opposite pattern compared to the mRNA expression patterns.
CONCLUSION: This study establishes a novel prognostic model for LUAD based on six ER stress-related genes, facilitating the prediction of LUAD prognosis. Additionally, NUPR1 was identified as a potential regulator of stress in LUAD.

Keywords:  Endoplasmic reticulum; Immune infiltration; Lung adenocarcinoma; Prognosis; Therapy

DOI:  https://doi.org/10.1186/s12920-023-01785-4
Clin Lung Cancer. 2023 Dec 01. pii: S1525-7304(23)00255-3. [Epub ahead of print]

Clinical and Genomic Characterization of Long-Term Responders Receiving Immune Checkpoint Blockade for Metastatic Non-Small-Cell Lung Cancer.

Paola Ghanem, Joseph C Murray, Melinda Hsu, Matthew Z Guo, David S Ettinger, Josephine Feliciano, Patrick Forde, Christine L Hann, Vincent K Lam, Benjamin Levy, Valsamo Anagnostou, Julie R Brahmer, Kristen A Marrone.

   OBJECTIVES: Understand from a real-world cohort the unique clinical and genomic determinants of a durable response to immune checkpoint inhibitors (ICIs).
MATERIALS AND METHODS: This is a retrospective study of patients with NSCLC who received any ICI-based regimen as first or second line therapy. Long-term responders (LTR) achieved an overall survival (OS) ≥ 3 years from time of treatment start, while nonresponders (NR) were patients who had an OS of 6 to 12 months from time of treatment start. Clinical and demographic covariables were collected from electronic medical records. Fisher's exact test and Mann-Whitney test were used to analyze the association of a long-term response to ICI in relation to clinical and genomic variables. All P-values were considered significant at P-value < .05.
RESULTS: A total of 72 patients were included in this study (LTR n = 37, NR n = 35). There were no significant differences in age, sex, race, and BMI between groups. The presence of liver metastases at the time of ICI initiation and PD-L1 status were not associated with LTR to ICIs. Patients in the LTR were more likely to experience irAEs at 3-,6- and 12-months. KRAS mutant tumors were numerically more common in the LTR group (n = 13 vs. 8).
CONCLUSION: We observe no strong clinical and biomarkers of a prolonged response to ICIs. Additional large prospective cohort studies are needed to investigate the genomic footprint of long-term responders.

Keywords:  Cancer genomics; Immunotherapy; Long-term response

DOI:  https://doi.org/10.1016/j.cllc.2023.11.012