bims-meluca 2023-10-01 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023‒10‒01
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer.
Salivary Lipids of Patients with Non-Small Cell Lung Cancer Show Perturbation with Respect to Plasma.
TIMP1 is an early biomarker for detection and prognosis of lung cancer.
Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.
Gene Expressions and High Lymphocyte Count May Predict Durable Clinical Benefits in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.
DSCC1 interacts with HSP90AB1 and promotes the progression of lung adenocarcinoma via regulating ER stress.
Nivolumab after Induction Chemotherapy in Previously Treated Non-Small-Cell Lung Cancer Patients with Low PD-L1 Expression.
Establishing a prognostic model based on immune-related genes and identification of BIRC5 as a potential biomarker for lung adenocarcinoma patients.
Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer.

BMC Pulm Med. 2023 Sep 25. 23(1): 360

Metformin induces ferroptosis through the Nrf2/HO-1 signaling in lung cancer.

Chengmin Deng, Lin Xiong, Yang Chen, Kaifeng Wu, Jie Wu.

  BACKGROUND: Metformin is the most frequently prescribed medication for the treatment of type II diabetes mellitus and has played an anti-tumor potential in a variety of cancer types. Metformin can inhibit the growth of many cancer cells through various mechanisms, including ferroptosis. However, it is still unclear whether metformin can induce ferroptosis in lung cancer.METHODS: This study evaluated the anti-tumor effect of metformin by detecting the levels of oxidative stress factors, the levels of ferrous ions, and the expression of ferroptosis-related genes in A549 and H1299 lung cancer cell lines treated with or without metformin.
RESULTS: The results showed that metformin treatment increased the levels of MDA, ROS and iron ions, while decreased the levels of GSH, T-SOD and CAT. Meanwhile, metformin treatment reduced the protein expression levels of Gpx4 and SLC7A11, Nrf2 and HO-1, while the addition of ferroptosis inhibitor ferrostatin-1 reversed the reduction.
CONCLUSIONS: These results demonstrated that metformin exerts anti-tumor effects by inducing ferroptosis through the Nrf2/HO-1 signaling pathway in lung cancer cells, providing a theoretical basis for drug therapy of lung cancer patients.

Keywords:  Ferroptosis; Lung cancer; Metformin; Nrf2/HO-1 signaling; Oxidative stress

DOI:  https://doi.org/10.1186/s12890-023-02655-6
Int J Mol Sci. 2023 Sep 19. pii: 14264. [Epub ahead of print]24(18):

Salivary Lipids of Patients with Non-Small Cell Lung Cancer Show Perturbation with Respect to Plasma.

Bo Young Hwang, Jae Won Seo, Can Muftuoglu, Ufuk Mert, Filiz Guldaval, Milad Asadi, Haydar Soydaner Karakus, Tuncay Goksel, Ali Veral, Ayse Caner, Myeong Hee Moon.

  A comprehensive lipid profile was analyzed in patients with non-small cell lung cancer (NSCLC) using nanoflow ultrahigh-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. This study investigated 297 and 202 lipids in saliva and plasma samples, respectively, comparing NSCLC patients to healthy controls. Lipids with significant changes (>2-fold, p < 0.05) were further analyzed in each sample type. Both saliva and plasma exhibited similar lipid alteration patterns in NSCLC, but saliva showed more pronounced changes. Total triglycerides (TGs) increased (>2-3-fold) in plasma and saliva samples. Three specific TGs (50:2, 52:5, and 54:6) were significantly increased in NSCLC for both sample types. A common ceramide species (d18:1/24:0) and phosphatidylinositol 38:4 decreased in both plasma and saliva by approximately two-fold. Phosphatidylserine 36:1 was selectively detected in saliva and showed a subsequent decrease, making it a potential biomarker for predicting lung cancer. We identified 27 salivary and 10 plasma lipids as candidate markers for NSCLC through statistical evaluations. Moreover, this study highlights the potential of saliva in understanding changes in lipid metabolism associated with NSCLC.

Keywords:  LC-ESI-MS/MS; NSCLC; lipidomic analysis; lung cancer; plasma; saliva

DOI:  https://doi.org/10.3390/ijms241814264
Clin Transl Med. 2023 Oct;13(10): e1391

TIMP1 is an early biomarker for detection and prognosis of lung cancer.

Ezequiel Dantas, Anirudh Murthy, Tanvir Ahmed, Mujmmail Ahmed, Shakti Ramsamooj, Maurice A Hurd, Tiffany Lam, Murtaza Malbari, Christopher Agrusa, Olivier Elemento, Chen Zhang, Darryl J Pappin, Timothy E McGraw, Brendon M Stiles, Nasser K Altorki, Marcus D Goncalves.

  BACKGROUND: Lung cancer remains the major cause of cancer-related deaths worldwide. Early stages of lung cancer are characterized by long asymptomatic periods that are ineffectively identified with the current screening programs. This deficiency represents a lost opportunity to improve the overall survival of patients. Serum biomarkers are among the most effective strategies for cancer screening and follow up.METHODS: Using bead-based multiplexing assays we screened plasma and tumours of the KrasG12D/+; Lkb1f/f (KL) mouse model of lung cancer for cytokines that could be used as biomarkers. We identified tissue inhibitor of metalloproteinase 1 (TIMP1) as an early biomarker and validated this finding in the plasma of lung cancer patients. We used immunohistochemistry (IHC), previously published single-cell RNA-seq and bulk RNA-seq data to assess the source and expression of TIMP1in the tumour. The prognostic value of TIMP1 was assessed using publicly available human proteomic and transcriptomic databases.
RESULTS: We found that TIMP1 is a tumour-secreted protein with high sensitivity and specificity for aggressive cancer, even at early stages in mice. We showed that TIMP1 levels in the tumour and serum correlate with tumour burden and worse survival in mice. We validated this finding using clinical samples from our institution and publicly available human proteomic and transcriptomic databases. These data support the finding that high tumour expression of TIMP1 correlates with an unfavorable prognosis in lung cancer patients.
CONCLUSION: TIMP1 is a suitable biomarker for lung cancer detection.

Keywords:  TIMP1; biomarkers; lung cancer; prognosis

DOI:  https://doi.org/10.1002/ctm2.1391
Commun Biol. 2023 Sep 23. 6(1): 977

Oncometabolite D-2-hydroxyglutarate-dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia.

Xinting Zhu, Juan Hao, Hong Zhang, Mengyi Chi, Yaxian Wang, Jinlu Huang, Rong Xu, Zhao Xincai, Bo Xin, Xipeng Sun, Jianping Zhang, Shumin Zhou, Dongdong Cheng, Ting Yuan, Jun Ding, Shuier Zheng, Cheng Guo, Quanjun Yang.

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

DOI: https://doi.org/10.1038/s42003-023-05366-0
Cancers (Basel). 2023 Sep 08. pii: 4480. [Epub ahead of print]15(18):

Gene Expressions and High Lymphocyte Count May Predict Durable Clinical Benefits in Patients with Advanced Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Mette T Mouritzen, Morten Ladekarl, Henrik Hager, Trine B Mattesen, Julie B Lippert, Malene S Frank, Anne K Nøhr, Ida B Egendal, Andreas Carus.

  BACKGROUND: Not all patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint inhibitors (ICIs). Therefore, we aimed to assess the predictive potential of gene expression profiling (GEP), peripheral immune cell counts, and clinical characteristics.METHODS: The primary endpoint of this prospective, observational study was a durable clinical benefit (DCB) defined as progression-free survival >6 months. In a subgroup with histological biopsies of sufficient quality (n = 25), GEP was performed using the nCounter® PanCancer IO 360 panel.
RESULTS: DCB was observed in 49% of 123 included patients. High absolute lymphocyte count (ALC) and absence of liver metastases were associated with DCB (OR = 1.95, p = 0.038 and OR = 0.36, p = 0.046, respectively). GEP showed clustering of differentially expressed genes according to DCB, and a strong association between PD-L1 assessed by GEP (CD274) and immunohistochemistry (IHC) was observed (p = 0.00013). The TGF-β, dendritic cell, and myeloid signature scores were higher for patients without DCB, whereas the JAK/STAT loss signature scores were higher for patients with DCB (unadjusted p-values < 0.05).
CONCLUSIONS: ALC above 1.01 × 109/L and absence of liver metastases were significantly associated with DCB in ICI-treated patients with NSCLC. GEP was only feasible in 20% of the patients. GEP-derived signatures may be associated with clinical outcomes, and PD-L1 could be assessed by GEP rather than IHC.

Keywords:  biomarkers; gene expression analysis; immune checkpoint inhibitors; liver metastases; lymphocyte count; non-small cell lung cancer

DOI:  https://doi.org/10.3390/cancers15184480
Cancer Cell Int. 2023 Sep 23. 23(1): 208

DSCC1 interacts with HSP90AB1 and promotes the progression of lung adenocarcinoma via regulating ER stress.

Xu Lin, Ye-Han Liu, Huan-Qi Zhang, Lin-Wen Wu, Qi Li, Jun Deng, Qingyi Zhang, Yuhong Yang, Chong Zhang, Yang-Ling Li, Jian Hu.

  Lung cancer is a leading cause of cancer-related deaths, and the most common type is lung adenocarcinoma (LUAD). LUAD is frequently diagnosed in people who never smoked, patients are always diagnosed at advanced inoperable stages, and the prognosis is ultimately poor. Thus, there is an urgent need for the development of novel targeted therapeutics to suppress LUAD progression. In this study, we demonstrated that the expression of DNA replication and sister chromatid cohesion 1 (DSCC1) was higher in LUAD samples than normal tissues, and the overexpression of DSCC1 or its coexpressed genes were highly correlated with poor outcomes of LUAD patients, highlighting DSCC1 might be involved in LUAD progression. Furthermore, the expression of DSCC1 was positively correlated with multiple genetic mutations which drive cancer development, including TP53, TTN, CSMD, and etc. More importantly, DSCC1 could promote the cell proliferation, stemness, EMT, and metastatic potential of LUAD cells. In addition, DSCC1 interacted with HSP90AB1 and promoted the progression of LUAD via regulating ER stress. Meanwhile, DSCC1 expression negatively correlated with immune cell infiltration in lung cancer, and DSCC1 positively regulated the expression of PD-L1 in LUAD cells. Collectively, this study revealed that DSCC1 is a novel therapeutic target to treat LUAD and a biomarker for predicting the efficiency of PD-1/PD-L1 blockade treatment.

Keywords:  DSCC1; HSP90AB1; Lung adenocarcinoma; Metastasis; PD-L1; Proliferation; Stemness

DOI:  https://doi.org/10.1186/s12935-023-03047-w
Cancers (Basel). 2023 Sep 07. pii: 4460. [Epub ahead of print]15(18):

Nivolumab after Induction Chemotherapy in Previously Treated Non-Small-Cell Lung Cancer Patients with Low PD-L1 Expression.

Beung-Chul Ahn, Charny Park, Sang-Jin Lee, Sehwa Hong, Ji-Eun Hwang, Kyoungsuk Kwon, Jin Young Kim, Kyung-Hee Kim, Hyae Young Kim, Geon Kook Lee, Youngjoo Lee, Ji-Youn Han.

  This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression.

Keywords:  adriamycin; cyclophosphamide; induction chemotherapy; nivolumab; transferrin receptor protein

DOI:  https://doi.org/10.3390/cancers15184460
BMC Cancer. 2023 Sep 23. 23(1): 897

Establishing a prognostic model based on immune-related genes and identification of BIRC5 as a potential biomarker for lung adenocarcinoma patients.

Qianhe Ren, Qifan Li, Chenye Shao, Pengpeng Zhang, Zhuangzhuang Hu, Jun Li, Wei Wang, Yue Yu.

  BACKGROUND: Lung adenocarcinoma (LUAD) is an extraordinarily malignant tumor, with rapidly increasing morbidity and poor prognosis. Immunotherapy has emerged as a hopeful therapeutic modality for lung adenocarcinoma. Furthermore, a prognostic model (based on immune genes) can fulfill the purpose of early diagnosis and accurate prognostic prediction.METHODS: Immune-related mRNAs (IRmRNAs) were utilized to construct a prognostic model that sorted patients into high- and low-risk groups. Then, the prediction efficacy of our model was evaluated using a nomogram. The differences in overall survival (OS), the tumor mutation landscape, and the tumor microenvironment were further explored between different risk groups. In addition, the immune genes comprising the prognostic model were subjected to single-cell RNA sequencing to investigate the expression of these immune genes in different cells. Finally, the functions of BIRC5 were validated through in vitro experiments.
RESULTS: Patients in different risk groups exhibited sharply significant variations in OS, pathway activity, immune cell infiltration, mutation patterns, and immune response. Single-cell RNA sequencing revealed that the expression level of BIRC5 was significantly high in T cells. Cell experiments further revealed that BIRC5 knockdown markedly reduced LUAD cell proliferation.
CONCLUSION: This model can function as an instrumental variable in the prognostic, molecular, and therapeutic prediction of LUAD, shedding new light on the optimal clinical practice guidelines for LUAD patients.

Keywords:  Immune genes; Immunotherapy; Prognosis; Risk signature; Tumor mutation burden; lung adenocarcinoma

DOI:  https://doi.org/10.1186/s12885-023-11249-8
J Cancer Res Clin Oncol. 2023 Sep 28.

Effectiveness of first-line anticancer treatment may predict treatment response in further lines in stage III/IV patients with non-small cell lung cancer.

Monika Bratova, Jana Skrickova, Magda Matusikova, Karolina Hrabcova, Libor Havel, Leona Koubkova, Michal Hrnciarik, Jana Krejci, Ondrej Fischer, Martin Svaton, Kristian Brat.

  PURPOSE: The aim of our study was to evaluate if therapeutic success in the first-line of anticancer treatments in patients with NSCLC may predict treatment success in the following lines.METHODS: We analyzed the data of patients with NSCLC stage III/IV from the TULUNG registry separately for chemotherapy, TKIs, ALK inhibitors, and immunotherapy in the first line during the years 2011-2019. "Succesful treatment " was defined as PFS ≥ 6 months, a "good responder " was a patient with ˃50% of "successful treatment " lines. Treatment responses were analyzed separately for each drug group. Descriptive statistics, Fisher exact test, Pearson Chi-Squared test, log-rank test, and univariate/multivariate logistic regression models were used.
RESULTS: The first-line TKI therapy was successful in 66.2%, while good responders accounted for 50.7% of the cohort and their rates were similar for all types of TKIs. First-line platinum-based chemotherapy was successful in 43.1% and 48.6% for combinations with pemetrexed and bevacizumab, respectively. Good responders accounted for 29.5% and 25.9%, respectively. In the group of ALK inhibitors, we observed treatment success in 52.3% of cases, while alectinib showed the highest effectiveness (up to 70%). Good responders constituted 50% of the group. In the first-line immunotherapy group, survival benefit was observed in 52.3%, and good responders constituted 52.3% of the cohort.
CONCLUSION: We concluded that the treatment success in first-line therapies in patients with NSCLC may predict survival benefits in the subsequent lines, particularly in EGFR- or ALK-positive disease and immunotherapy-treated patients.

Keywords:  Anticancer treatment; Effectiveness; Non-small cell lung cancer; Overall survival; Progression-free survival

DOI:  https://doi.org/10.1007/s00432-023-05431-5