bims-meluca 2019-10-06 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2019–10–06
six 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

Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells.
Correlation of body composition by computerized tomography and metabolic parameters with survival of nivolumab-treated lung cancer patients.
"NRF2 Addiction" in Lung Cancer Cells and Its Impact on Cancer Therapy.
Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.
Elevated levels of pre-treatment lactate dehydrogenase are an unfavorable predictor factor in patients with EML4-ALK rearrangement non-small cell lung cancer treated with crizotinib.
The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice.

Mol Cell. 2019 Sep 24. pii: S1097-2765(19)30683-5. [Epub ahead of print]

Metabolic Diversity in Human Non-Small Cell Lung Cancer Cells.

Pei-Hsuan Chen, Ling Cai, Kenneth Huffman, Chendong Yang, Jiyeon Kim, Brandon Faubert, Lindsey Boroughs, Bookyung Ko, Jessica Sudderth, Elizabeth A McMillan, Luc Girard, Dong Chen, Michael Peyton, Misty D Shields, Bo Yao, David S Shames, Hyun Seok Kim, Brenda Timmons, Ikuo Sekine, Rebecca Britt, Stephanie Weber, Lauren A Byers, John V Heymach, Jing Chen, Michael A White, John D Minna, Guanghua Xiao, Ralph J DeBerardinis.

  Intermediary metabolism in cancer cells is regulated by diverse cell-autonomous processes, including signal transduction and gene expression patterns, arising from specific oncogenotypes and cell lineages. Although it is well established that metabolic reprogramming is a hallmark of cancer, we lack a full view of the diversity of metabolic programs in cancer cells and an unbiased assessment of the associations between metabolic pathway preferences and other cell-autonomous processes. Here, we quantified metabolic features, mostly from the 13C enrichment of molecules from central carbon metabolism, in over 80 non-small cell lung cancer (NSCLC) cell lines cultured under identical conditions. Because these cell lines were extensively annotated for oncogenotype, gene expression, protein expression, and therapeutic sensitivity, the resulting database enables the user to uncover new relationships between metabolism and these orthogonal processes.

Keywords:  (13)C stable isotope labeling; cancer metabolism; cell lines; gene expression; glucose; glutamine; non-small cell lung cancer; oncogenotypes; protein expression; therapeutic sensitivity

DOI:  https://doi.org/10.1016/j.molcel.2019.08.028
Cancer Manag Res. 2019 ;11 8201-8207

Correlation of body composition by computerized tomography and metabolic parameters with survival of nivolumab-treated lung cancer patients.

Valentina Magri, Teodor Gottfried, Mattia Di Segni, Damien Urban, Michael Peled, Sameh Daher, Ronen Stoff, Jair Bar, Amir Onn.

   Purpose: Weight loss is a well-recognized prognostic parameter for survival of lung cancer patients. Computerized-tomography (CT)-based analysis of body composition and blood-based metabolic evaluation are promising prognostic tools. We aimed to assess the correlation between albumin, body mass index (BMI), skeletal muscle mass index (SMI), fat-free mass index (FFMI), fat mass index (FMI) and weight change, as well as their correlation with survival of lung cancer patients on nivolumab treatment.
Methods: Data were retrospectively collected. Weight was measured at a diagnosis of stage 4 disease and before start of nivolumab. Albumin levels were measured before starting nivolumab. BMI, SMI, FFMI, and FMI were evaluated from CT scans performed at start of nivolumab. Overall survival (OS) was from starting of nivolumab to death or censured at last follow-up. Statistical analysis was done to identify correlation between the various factors and between those factors and survival.
Results: Forty-six patients with advanced non-small cell lung cancer (NSCLC) were included. Median follow-up was 22 months. Pathology was Adenocarcinoma/Squamous/non-other specified in 25/15/6 respectively. All patients received nivolumab as an advanced-line treatment for stage IV NSCLC. We observed a significant correlation of weight loss (P=0.01, HR=2.85) and albumin (P=0.043, HR=0.34) with OS in multivariate analysis. A significant correlation was found between BMI to SMI, FFMI, FMI, and weight change.
Conclusion: Weight loss and low albumin levels are significant negative prognostic factors for NSCLC patients on immunotherapy. CT-based parameters of body composition remain to be proven as more reliable than standard clinical parameters.

Keywords:  BMI; albumin; immunotherapy; prognosis; weight

DOI:  https://doi.org/10.2147/CMAR.S210958
Cancer Lett. 2019 Sep 28. pii: S0304-3835(19)30488-4. [Epub ahead of print]

"NRF2 Addiction" in Lung Cancer Cells and Its Impact on Cancer Therapy.

Ahmed Hammad, Akhileshwar Namani, Mohamed Elshaer, Xiu Jun Wang, Xiuwen Tang.

  Nuclear factor erythroid 2-like factor 2 (NRF2) is a master regulator of the antioxidant enzymes and the detoxification proteins that play major roles in redox homeostasis. Although it plays a protective role against tumorigenesis, emerging evidence has shown that the NRF2 pathway is frequently altered in different types of cancer, including lung cancer. NRF2 activation influences many of the hallmarks of cancer and their signaling pathways, mainly apoptosis, proliferation, angiogenesis, metastasis, and metabolic reprogramming to establish cellular metabolic processes leading to "NRF2 addiction" in lung cancer cells. Intriguingly, constitutive activation of NRF2 promotes cancer development as well as resistance to chemotherapy and radiotherapy, and these malignant phenotypes lead to a poor prognosis in lung cancer patients. Therefore, targeted inhibition of the NRF2 together with traditional chemotherapy, radiotherapy, and immunotherapy, may be a promising approach to improving the survival rates of the NRF2-addicted lung cancer cases. Here we summarize the recent advances in NRF2-addicted lung cancer.

Keywords:  Cancer metabolism; Inhibitors; KEAP1; Tumor progression; chemoresistance

DOI:  https://doi.org/10.1016/j.canlet.2019.09.016
Cancers (Basel). 2019 Oct 02. pii: E1488. [Epub ahead of print]11(10):

Decoupling of Nrf2 Expression Promotes Mesenchymal State Maintenance in Non-Small Cell Lung Cancer.

John A Haley, Christian F Ruiz, Emily D Montal, Daifeng Wang, John D Haley, Geoffrey D Girnun.

  Epithelial mesenchymal transition is a common mechanism leading to metastatic dissemination and cancer progression. In an effort to better understand this process we found an intersection of Nrf2/NLE2F2 (Nrf2), epithelial mesenchymal transition (EMT), and metabolic alterations using multiple in vitro and in vivo approaches. Nrf2 is a key transcription factor controlling the expression of redox regulators to establish cellular redox homeostasis. Nrf2 has been shown to exert both cancer inhibitory and stimulatory activities. Using multiple isogenic non-small cell lung cancer (NSCLC) cell lines, we observed a reduction of Nrf2 protein and activity in a prometastatic mesenchymal cell state and increased reactive oxygen species. Knockdown of Nrf2 promoted a mesenchymal phenotype and reduced glycolytic, TCA cycle and lipogenic output from both glucose and glutamine in the isogenic cell models; while overexpression of Nrf2 promoted a more epithelial phenotype and metabolic reactivation. In both Nrf2 knockout mice and in NSCLC patient samples, Nrf2low was co-correlated with markedly decreased expression of glycolytic, lipogenic, and mesenchymal RNAs. Conversely, Nrf2high was associated with partial mesenchymal epithelial transition and increased expression of metabolic RNAs. The impact of Nrf2 on epithelial and mesenchymal cancer cell states and metabolic output provide an additional context to Nrf2 function in cancer initiation and progression, with implications for therapeutic inhibition of Nrf2 in cancer treatment.

Keywords:  Nrf2; TCA cycle; epithelial mesenchymal transition; glycolysis; lipogenesis; redox signaling

DOI:  https://doi.org/10.3390/cancers11101488
Cancer Manag Res. 2019 ;11 8191-8200

Elevated levels of pre-treatment lactate dehydrogenase are an unfavorable predictor factor in patients with EML4-ALK rearrangement non-small cell lung cancer treated with crizotinib.

Hongge Liang, Di Ma, Yan Xu, Jing Zhao, Minjiang Chen, Xiaoyan Liu, Wei Zhong, Junling Li, Mengzhao Wang.

   Background: Targeted therapy is an important treatment for advanced non-small cell lung cancer (NSCLC) patients with specific genetic mutations, crizotinib can prolong survival in advanced NSCLC patients with echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement. We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with EML4-ALK rearrangement NSCLC receiving treatment with crizotinib.
Methods: Advanced (stage IIIb-IV) NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled between January 2007 and January 2016 at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences.
Results: Overall, 212 patients were enrolled. Kaplan-Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs 14.1 months, HR =1.251, CI: 1.008-1.553, P=0.004) was significantly associated with shorter PFS, while the post-treatment mean-LDH level (13.3 vs 14.3 months, HR=1.439, 95% CI: 0.994-2.082, P=0.970) was not significantly associated with PFS. Cox proportional hazards model also identified that pre-treatment LDH level (HR=2.085, 95% CI: 1.150-3.781, P=0.016) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase (OR=6.712, 95% CI 3.395-13.273, P<0.01), creatine kinase isoenzyme (OR=6.297, 95% CI 2.953-13.427, P<0.01), and hemoglobin (OR=4.163, 1.741-9.956, P<0.001).
Conclusion: An elevated pre-treatment serum LDH level (>250 U/L) was significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level was not significantly associated with PFS, which related to adverse events including muscle damage and anemia.

Keywords:  crizotinib; echinoderm microtubule-associated protein-like 4–anaplastic lymphoma kinase; lactate dehydrogenase; non-small cell lung cancer; progression-free survival

DOI:  https://doi.org/10.2147/CMAR.S213572
JCI Insight. 2019 Oct 03. pii: 127647. [Epub ahead of print]4(19):

The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice.

Marielle Breau, Amal Houssaini, Larissa Lipskaia, Shariq Abid, Emmanuelle Born, Elisabeth Marcos, Gabor Czibik, Aya Attwe, Delphine Beaulieu, Alberta Palazzo, Jean-Michel Flaman, Brigitte Bourachot, Guillaume Collin, Jeanne Tran Van Nhieu, David Bernard, Fatima Mechta-Grigoriou, Serge Adnot.

  Oxidative stress is a major contributor to chronic lung diseases. Antioxidants such as N-acetylcysteine (NAC) are broadly viewed as protective molecules that prevent the mutagenic effects of reactive oxygen species. Antioxidants may, however, increase the risk of some forms of cancer and accelerate lung cancer progression in murine models. Here, we investigated chronic NAC treatment in aging mice displaying lung oxidative stress and cell senescence due to inactivation of the transcription factor JunD, which is downregulated in diseased human lungs. NAC treatment decreased lung oxidative damage and cell senescence and protected from lung emphysema but concomitantly induced the development of lung adenocarcinoma in 50% of JunD-deficient mice and 10% of aged control mice. This finding constitutes the first evidence to our knowledge of a carcinogenic effect of antioxidant therapy in the lungs of aged mice with chronic lung oxidative stress and warrants the utmost caution when considering the therapeutic use of antioxidants.

Keywords:  COPD; Cancer; Lung cancer; Oncology; Pulmonology

DOI:  https://doi.org/10.1172/jci.insight.127647